Therapeutic agents useful for treating pain

ABSTRACT

Compounds of formulae: 
     
       
         
         
             
             
         
       
     
     where X is S or O and Ar 2 , R 1 , R 2 , R 3 , R 8 , n, m, t, and v are disclosed herein, or a pharmaceutically acceptable salt thereof (a “3-substituted Pyridyl Compound”), compositions comprising an effective amount of a 3-substituted Pyridyl Compound, and methods for treating or preventing pain, urinary incontinence, an ulcer, inflammatory-bowel disease, irritable-bowel syndrome, an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression in an animal comprising administering to an animal in need thereof an effective amount of a 3-substituted Pyridyl Compound are disclosed herein.

This application claims the benefit of U.S. provisional application No.60/491,518, filed Aug. 1, 2003, and International patent application no.PCT/US2004/024753, filed Jul. 30, 2004, the disclosure of eachapplication being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to 3-substituted Pyridyl Compounds,compositions comprising an effective amount of a 3-substituted PyridylCompound and methods for treating or preventing a condition such as paincomprising administering to an animal in need thereof an effectiveamount of a 3-substituted Pyridyl Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or central nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at both Group I mGluRs (mGluR1 andmGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloidreceptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5reduces pain, as shown by in vivo treatment with antibodies selectivefor either mGluR1 or mGluR5, where neuropathic pain in rats wasattenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It hasalso been shown that antisense oligonucleotide knockdown of mGluR1alleviates both neuropathic and inflammatory pain (M. E. Fundytus etal., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytuset al., Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Smallmolecule antagonists for mGluR5-attenuated pain in in vivo animal modelsare disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9(2000) and A. Dogrul et al, Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.,gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDAantagonists (e.g., ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.,fluoxetine, sertraline and amitriptyline).

Pain has been traditionally managed by administering non-opioidanalgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id

Urinary incontinence (“UI”) is uncontrollable urination, generallycaused by bladder-detrusor-muscle instability. UI affects people of allages and levels of physical health, both in health care settings and inthe community at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects. For example,drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract hasbeen eroded by stomach acids or digestive juices. The sores aretypically well-defined round or oval lesions primarily occurring in thestomach and duodenum. About 1 in 10 people develop an ulcer. Ulcersdevelop as a result of an imbalance between acid-secretory factors, alsoknown as “aggressive factors,” such as stomach acid, pepsin, andHelicobacter pylori infection, and local mucosal-protective factors,such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres toepithelial cells and is believed to form a protective coating at thebase of an ulcer to promote healing. Sucraflate, however, can causeconstipation, dry mouth, and interfere with the absorption of otherdrugs.

Antibiotics are used when Helicobacter pylori is the underlying cause ofthe ulcer. Often antibiotic therapy is coupled with the administrationof bismuth compounds such as bismuth subsalicylate and colloidal bismuthcitrate. The bismuth compounds are believed to enhance secretion ofmucous and HCO₃ ⁻, inhibit pepsin activity, and act as an antibacterialagainst H. pylori. Ingestion of bismuth compounds, however, can lead toelevated plasma concentrations of Bi⁺³ and can interfere with theabsorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acidand stimulate the secretion of mucous and bicarbonate and are also usedto treat ulcers, especially ulcers in patients who require nonsteroidalanti-inflammatory drugs. Effective oral doses of prostaglandinanalogues, however, can cause diarrhea and abdominal cramping. Inaddition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers.Carbenoxolone appears to alter the composition and quantity of mucous,thereby enhancing the mucosal barrier. Carbenoxolone, however, can leadto Na⁺ and fluid retention, hypertension, hypokalemia, and impairedglucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapinecan also be used to reduce acid secretion and treat ulcers. Side effectsof muscarinic cholinergic antagonists include dry mouth, blurred vision,and constipation. The Merck Manual of Medical Information 496-500 (R.Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis ofTherapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominalpain, fever, loss of appetite, and weight loss. Complications associatedwith Crohn's disease include the development of intestinal obstructions,abnormal connecting channels (fistulas), and abscesses. The risk ofcancer of the large intestine is increased in people who have Crohn'sdisease. Often Crohn's disease is associated with other disorders suchas gallstones, inadequate absorption of nutrients, amyloidosis,arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyodermagangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primarysclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine. Generally, the drug is takenorally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptomsof Crohn's disease. The antibiotic metronidazole is often administeredwhen the disease affects the large intestine or causes abscesses andfistulas around the anus. Long-term use of metronidazole, however, candamage nerves, resulting in pins-and-needles sensations in the arms andlegs. Sulfasalazine and chemically related drugs can suppress mildinflammation, especially in the large intestine. These drugs, however,are less effective in sudden, severe flare-ups. Corticosteroids, such asprednisone, reduce fever and diarrhea and relieve abdominal pain andtenderness. Long-term corticosteroid therapy, however, invariablyresults in serious side effects such as high blood-sugar levels,increased risk of infection, osteoporosis, water retention, andfragility of the skin. Drugs such as azathioprine and mercaptourine cancompromise the immune system and are often effective for Crohn's diseasein patients that do not respond to other drugs. These drugs, however,usually need 3 to 6 months before they produce benefits and can causeserious side effects such as allergy, pancreatitis, and lowwhite-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered. Sulfasalazine, olsalazine,prednisone, or mesalamine can be used to reduce inflammation.Azathioprine and mercaptopurine have been used to maintain remissions inulcerative-colitis patients who would otherwise need long-termcorticosteroid treatment. In severe cases of ulcerative colitis thepatient is hospitalized and given corticosteroids intravenously. Peoplewith severe rectal bleeding can require transfusions and intravenousfluids. If toxic colitis develops and treatments fail, surgery to removethe large intestine can be necessary. Non-emergency surgery can beperformed if cancer is diagnosed, precancerous lesions are detected, orunremitting chronic disease would otherwise make the person an invalidor dependent on high doses of corticosteroids. Complete removal of thelarge intestine and rectum permanently cures ulcerative colitis. TheMerck Manual of Medical Information 530-532 (R. Berkow ed., 1997) andGoodman and Gilman's The Pharmacological Basis of Therapeutics (J.Hardman and L. Limbird eds., 9^(th) ed. 1996).

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more women than men. In IBS stimulisuch as stress, diet, drugs, hormones, or irritants can cause thegastrointestinal tract to contract abnormally. During an episode of IBS,contractions of the gastrointestinal tract become stronger and morefrequent, resulting in the rapid transit of food and feces through thesmall intestine, often leading to diarrhea. Cramps result from thestrong contractions of the large intestine and increased sensitivity ofpain receptors in the large intestine.

There are two major types of IBS. The first type, spastic-colon type, iscommonly triggered by eating, and usually produces periodic constipationand diarrhea with pain. Mucous often appears in the stool. The pain cancome in bouts of continuous dull aching pain or cramps, usually in thelower abdomen. The person suffering from spastic-colon type IBS can alsoexperience bloating, gas, nausea, headache, fatigue, depression,anxiety, and difficulty concentrating. The second type of IBS usuallyproduces painless diarrhea or constipation. The diarrhea can beginsuddenly and with extreme urgency. Often the diarrhea occurs soon aftera meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the addictive substance.U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixedopiate agonist/antagonist to treat cocaine and opiate addiction. U.S.Pat. No. 5,232,934 to Downs discloses administration of3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and5,198,459 to Imperato et al. disclose using a serotonin antagonist totreat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al.discloses infusing BDNF or NT-4 growth factors to inhibit or reverseneurological adaptive changes that correlate with behavioral changes inan addicted individual. U.S. Pat. No. 5,762,925 to Sagan disclosesimplanting encapsulated adrenal medullary cells into an animal's centralnervous system to inhibit the development of opioid intolerance. U.S.Pat. No. 6,204,284 to Beer et al. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akineticstate in which patients are incapable of caring for themselves. Deathfrequently results from complications of immobility, includingaspiration pneumonia or pulmonary embolism. Drugs commonly used for thetreatment of Parkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

Currently, benzodiazepines are the most commonly used anti-anxietyagents for generalized anxiety disorder. Benzodiazepines, however, carrythe risk of producing impairment of cognition and skilled motorfunctions, particularly in the elderly, which can result in confusion,delerium, and falls with fractures. Sedatives are also commonlyprescribed for treating anxiety. The azapirones, such as buspirone, arealso used to treat moderate anxiety. The azapirones, however, are lessuseful for treating severe anxiety accompanied with panic attacks.

Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital,phenyloin, primidone, valproic acid, trimethadione, benzodiazepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

Symptoms of strokes vary depending on what part of the brain isaffected. Symptoms include loss or abnormal sensations in an arm or legor one side of the body, weakness or paralysis of an arm or leg or oneside of the body, partial loss of vision or hearing, double vision,dizziness, slurred speech, difficulty in thinking of the appropriateword or saying it, inability to recognize parts of the body, unusualmovements, loss of bladder control, imbalance, and falling, andfainting. The symptoms can be permanent and can be associated with comaor stupor. Examples of drugs for treating strokes include anticoagulantssuch as heparin, drugs that break up clots such as streptokinase ortissue plasminogen activator, and drugs that reduce swelling such asmannitol or corticosteroids. The Merck Manual of Medical Information352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching.Conventionally, pruritus is treated by phototherapy with ultraviolet Bor PUVA or with therapeutic agents such as naltrexone, nalmefene,danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292 (2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anxiolytic and anti-depressant activity in in vivo animal models(E. Tatarczynska et al., Br. J. Pharmacol. 132 (7):1423-1430 (2001) andP. J. M. Will et al., Trends in Pharmacological Sciences 22 (7):331-37(2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41 (4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22 (7):33′-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4 (9):873-74 (2001)).

European patent publication no. EP 1 122 242 discloses cyanophenyl andnitrophenyl compounds allegedly having antiandrogen activity.

Japanese patent application no. 2001-328938 discloses cyanophenylderivatives that allegedly have anti-androgen activity and are usefulfor the treatment of prostrate cancer and prostrate hypertrophy.

Japanese patent application no. 2001-261657 discloses cyanophenylderivatives that allegedly have anti-androgen activity.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, UI, an ulcer, IBD, IBS, an addictivedisorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke,a seizure, a pruritic condition, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting; dyskinesia,or depression.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds having the formula (I):

and pharmaceutically acceptable salts thereof, where:

X is S or O;

Ar₂ is

R₁ is —CF₃, —NO₂, or —CN;

each R₂ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c)-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇,—COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₉ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, or CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OH₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

n is an integer ranging from 0 to 3;

m is 0 or 1;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5, and

t is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(II):

and pharmaceutically acceptable salts thereof, where:

X is O or S;

Ar₂ is

R₁ is —CF₃, —NO₂, or —CN;

each R₂ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;

(b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl; —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇,—COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇; —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₉ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, or CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇,—COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

n is an integer ranging from 0 to 3;

m is 0 or 1;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

t is an integer ranging from 0 to 2.

A compound of formula (I) and (II) or a pharmaceutically acceptable saltthereof (a “3-substituted Pyridyl Compound”) is useful for treating orpreventing pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression' epression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a 3-substituted Pyridyl Compound and a pharmaceuticallyacceptable carrier or excipient. The compositions are useful fortreating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a 3-substituted Pyridyl Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a 3-substituted Pyridyl Compound.

The invention still further relates to methods for inhibiting VanilloidReceptor 1 (“VR1”) function in a cell, comprising contacting a cellcapable of expressing VR1 with an effective amount of a 3-substitutedPyridyl Compound.

The invention still further relates to methods for inhibiting mGluR5function in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a 3-substituted Pyridyl Compound.

The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a 3-substituted Pyridyl Compound.

The invention still further relates to methods for preparing acomposition, comprising the step of admixing a 3-substituted PyridylCompound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a 3-substituted Pyridyl Compound.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 3-Substituted PyridylCompounds of Formula (I)

As stated above, the present invention encompasses compounds of Formula(I):

and pharmaceutically acceptable salts thereof, where Ar₂, R₁, R₂, R₃,R₈, n, m, and t are defined above for the 3-substituted PyridylCompounds of formula (I).

In one embodiment, Ar₂ is

where R₉ and r are defined above for the 3-substituted Pyridyl Compoundsof formula (I).

In one embodiment, Ar₂ is

where r is 1 and R₉ is in the 4-position of the phenyl ring.

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (I).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (I).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (I).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (I).

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, n is 0.

In another embodiment, n is 1 and R₂ is -halo, —OH, or —NH₂.

In another embodiment, n is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n is 1 and R₂ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1, R₃ is —CH₃, and the carbon atom to whichthe R₃ is attached is in the (R)-configuration.

In another embodiment, m is 1, R₃ is —CH₃, and the carbon atom to whichthe R₃ is attached is in the (S)-configuration.

4.2 3-Substituted Pyridyl Compounds of Formula (II)

The present invention also encompasses compounds of formula (II):

and pharmaceutically acceptable salts thereof, where Ar₂, R₁, R₂, R₃,R₈, n, m, and t are defined above for the 3-substituted PyridylCompounds of formula (II).

In another embodiment, Ar₂ is

where R₉ and r are defined above for the 3-substituted Pyridyl Compoundsof formula (II).

In one embodiment, Ar₂ is

where r is 1 and R₉ is in the 4-position of the phenyl ring.

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (II).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (II).

In another embodiment, Ar₂ is

where R₁₁ and r are defined above for the 3-substituted PyridylCompounds of formula (II).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula (II).

In another embodiment, Ar₂ is

where R₁₁ and q are defined above for the 3-substituted PyridylCompounds of formula

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, n is 0.

In another embodiment, n is 1 and R₂ is -halo, —OH, or —NH₂.

In another embodiment, n is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n is 1 and R₂ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, -(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1, R₃ is —CH₃, and the carbon atom to whichthe R₃ is attached is in the (R)-configuration.

In another embodiment, m is 1, R₃ is —CH₃, and the carbon atom to whichthe R₃ is attached is in the (S)-configuration.

4.3 3-Substituted Pyridyl Compounds of Formulas (I) and (II)

Certain 3-substituted Pyridyl Compounds may have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. A3-substituted Pyridyl Compound can be in the form of an optical isomeror a diastereomer. Accordingly, the invention encompasses 3-substitutedPyridyl Compounds and their uses as described herein in the form oftheir optical isomers, diasteriomers, and mixtures thereof, including aracemic mixture.

In the 3-substituted Pyridyl Compounds each R₃ can be on any carbon ofthe piperazine ring. In one embodiment, the 3-substituted PyridylCompounds have only one R₃ group, and that R₃ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridyl group.In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, and that R₃ group is attached to a carbon atom adjacent to thenitrogen atom attached to the phenethyl or phenpropyl group.

In another embodiment, two R₃ groups are on a single atom of thepiperazine ring. In another embodiment, an R₃ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridyl groupand another R₃ group is attached to a carbon atom adjacent to thenitrogen atom attached to the phenethyl or phenpropyl group.

In another embodiment, the 3-substituted Pyridyl Compound has two R₃groups, each being attached to a different carbon atom adjacent to anitrogen atom attached to the pyridyl group. In another embodiment, the3-substituted Pyridyl Compound has two R₃ groups, each being attached toa different carbon atom adjacent to a nitrogen atom attached to thephenethyl or phenpropyl group.

In one embodiment, where the 3-substituted Pyridyl Compound has one ortwo R₃ groups, the carbon atom to which an R₃ group is attached has the(R) configuration. In another embodiment, where the 3-substitutedPyridyl Compound has one or two R₃ groups, the carbon atom to which theR₃ group is attached has the (S) configuration. In another embodiment,the 3-substituted Pyridyl Compound has one or two R₃ groups, and atleast one of the carbon atoms to which an R₃ group is attached has the(R) configuration. In another embodiment, the 3-substituted PyridylCompound has one or two R₃ groups, and at least one of the carbon atomsto which an R₃ group is attached has the (S) configuration.

In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, and an R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl group, and the carbon to which theR₃ group is attached is in the (R) configuration. In another embodiment,the 3-substituted Pyridyl Compound has one or two R₃ groups, an R₃ groupis attached to a carbon atom adjacent to a nitrogen attached to thepyridyl group, the carbon to which the R₃ group is attached is in the(R) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substitutedwith one or more halo groups. In another embodiment, the 3-substitutedPyridyl Compound has one or two R₃ groups, an R₃ group is attached to acarbon atom adjacent to a nitrogen attached to the pyridyl group, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —CH₃. In another embodiment, the 3-substituted PyridylCompound has one or two R₃ groups, an R₃ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the pyridyl group, the carbon to which the R₃ groupis attached is in the (R) configuration, and R₃ is —CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the phenethyl or phenpropyl group, and thecarbon to which the R₃ group is attached is in the (R) configuration. Inanother embodiment, the 3-substituted Pyridyl Compound has one or two R₃groups, an R₃ group is attached to a carbon atom adjacent to a nitrogenattached to the phenethyl or phenpropyl group, the carbon to which theR₃ group is attached is in the (R) configuration, and R₃ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CH₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl group, and the carbon to which theR₃ group is attached is in the (S) configuration. In another embodiment,the 3-substituted Pyridyl Compound has one or two R₃ groups, an R₃ groupis attached to a carbon atom adjacent to a nitrogen attached to thepyridyl group, the carbon to which the R₃ group is attached is in the(S) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substitutedwith one or more halo groups. In another embodiment, the 3-substitutedPyridyl Compound has one or two R₃ groups, an R₃ group is attached to acarbon atom adjacent to a nitrogen attached to the pyridyl group, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —CH₃. In another embodiment, the 3-substituted PyridylCompound has one or two R₃ groups, an R₃ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the pyridyl group, the carbon to which the R₃ groupis attached is in the (S) configuration, and R₃ is —CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the phenethyl or phenpropyl group, and thecarbon to which the R₃ group is attached is in the (S) configuration. Inanother embodiment, the 3-substituted Pyridyl Compound has one or two R₃groups, an R₃ group is attached to a carbon atom adjacent to a nitrogenattached to the phenethyl or phenpropyl group, the carbon to which theR₃ group is attached is in the (S) configuration, and R₃ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the 3-substituted Pyridyl Compound has one or twoR₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CH₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has oneor two R₃ groups, an R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl group, and the carbon to which theR₃ group is attached is in the (R) configuration. In another embodiment,the 3-substituted Pyridyl Compound has only one R₃ group, the R₃ groupis attached to a carbon atom adjacent to a nitrogen attached to thepyridyl group, the carbon to which the R₃ group is attached is in the(R) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substitutedwith one or more halo groups. In another embodiment, the 3-substitutedPyridyl Compound has only one R₃ group, the R₃ group is attached to acarbon atom adjacent to a nitrogen attached to the pyridyl group, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the pyridyl group, the carbon to which the R₃ groupis attached is in the (R) configuration, and R₃ is —CF₃. In anotherembodiment, the 3-substituted Pyridyl Compound has only one R₃ group,the R₃ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl group, the carbon to which the R₃ group isattached is in the (R) configuration, and R₃ is —CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the phenethyl or phenpropyl group, and thecarbon to which the R₃ group is attached is in the (R) configuration. Inanother embodiment, the 3-substituted Pyridyl Compound has only one R₃group, the R₃ group is attached to a carbon atom adjacent to a nitrogenattached to the—phenethyl or phenpropyl group, the carbon to which theR₃ group is attached is in the (R) configuration, and R₃ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CH₃. In another embodiment, the 3-substituted Pyridyl Compound has onlyone R₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has onlyone R₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (R) configuration, and R₃ is—CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl group, and the carbon to which theR₃ group is attached is in the (S) configuration. In another embodiment,the 3-substituted Pyridyl Compound has only one R₃ group, the R₃ groupis attached to a carbon atom adjacent to a nitrogen attached to thepyridyl group, the carbon to which the R₃ group is attached is in the(S) configuration, and R₃ is —(C₁-C₄)alkyl unsubstituted or substitutedwith one or more halo groups. In another embodiment, the 3-substitutedPyridyl Compound has only one R₃ group, the R₃ group is attached to acarbon atom adjacent to a nitrogen attached to the pyridyl group, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —CH₃. In another embodiment, the 3-substituted PyridylCompound has only one R₃ group, the R₃ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has onlyone R₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the pyridyl group, the carbon to which the R₃ groupis attached is in the (S) configuration, and R₃ is —CH₂ CH₃.

In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen atom attached to the phenethyl or phenpropyl group, and thecarbon to which the R₃ group is attached is in the (S) configuration. Inanother embodiment, the 3-substituted Pyridyl Compound has only one R₃group, the R₃ group is attached to a carbon atom adjacent to a nitrogenattached to the phenethyl or phenpropyl group, the carbon to which theR₃ group is attached is in the (S) configuration, and R₃ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the 3-substituted Pyridyl Compound has only oneR₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CH₃. In another embodiment, the 3-substituted Pyridyl Compound has onlyone R₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CF₃. In another embodiment, the 3-substituted Pyridyl Compound has onlyone R₃ group, the R₃ group is attached to a carbon atom adjacent to anitrogen attached to the phenethyl or phenpropyl group, the carbon towhich the R₃ group is attached is in the (S) configuration, and R₃ is—CH₂ CH₃.

Optical isomers of the 3-substituted Pyridyl Compounds can be obtainedby known techniques such as chiral chromatography or formation ofdiastereomeric salts from an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of a3-substituted Pyridyl Compound can be replaced by an isotope of thehydrogen, carbon or other atoms. Such compounds, which are encompassedby the present invention, are useful as research and diagnostic tools inmetabolism pharmacokinetic studies and in binding assays.

Illustrative 3-substituted Pyridyl Compounds are listed below in Tables1-12.

TABLE 1 (III)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ A1—CF₃ -tert-butyl A2 —CF₃ -iso-butyl A3 —CF₃ -sec-butyl A4 —CF₃-cyclohexyl A5 —CF₃ -tert-butoxy A6 —CF₃ -iso-propoxCy A7 —CF₃ —CF₃ A8—CF₃ —CH₃ A9 —CF₃ —CH₂CF₃ A10 —CF₃ —OCF₃ A11 —CF₃ —OCH₃ A12 —CF₃ —Cl A13—CF₃ —Br A14 —CF₃ —I A15 —CF₃ -n-butyl A16 —CF₃ -n-propyl A17 —CF₃-iso-propyl A18 —CF₃ —C₆H₅ A19 —CF₃ —H A20 —NO₂ -tert-butyl A21 —NO₂-iso-butyl A22 —NO₂ -sec-butyl A23 —NO₂ -cyclohexyl A24 —NO₂-tert-butoxy A25 —NO₂ -iso-propoxy A26 —NO₂ —CF₃ A27 —NO₂ —CH₃ A28 —NO₂—CH₂CF₃ A29 —NO₂ —OCF₃ A30 —NO₂ —OCH₃ A31 —NO₂ —Cl A32 —NO₂ —Br A33 —NO₂—I A34 —NO₂ -n-butyl A35 —NO₂ -n-propyl A36 —NO₂ -iso-propyl A37 —NO₂—C₆H₅ A38 —NO₂ —H A39 —CN -tert-butyl A40 —CN -iso-butyl A41 —CN-sec-butyl A42 —CN -cyclohexyl A43 —CN -tert-butoxy A44 —CN -iso-propoxyA45 —CN —CF₃ A46 —CN —CH₃ A47 —CN —CH₂CF₃ A48 —CN —OCF₃ A49 —CN —OCH₃A50 —CN —Cl A51 —CN —Br A52 —CN —I A53 —CN -n-butyl A54 —CN -n-propylA55 —CN -iso-propyl A56 —CN —C₆H₅ A57 —CN —H

TABLE 2 (IV)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ B1(a) and (b) —CF₃ -tert-butyl B2 (a) and (b) —CF₃ -iso-butyl B3 (a) and(b) —CF₃ -sec-butyl B4 (a) and (b) —CF₃ -cyclohexyl B5 (a) and (b) —CF₃-tert-butoxy B6 (a) and (b) —CF₃ -iso-propoxy B7 (a) and (b) —CF₃ —CF₃B8 (a) and (b) —CF₃ —CH₃ B9 (a) and (b) —CF₃ —CH₂CF₃ B10 (a) and (b)—CF₃ —OCF₃ B11 (a) and (b) —CF₃ —OCH₃ B12 (a) and (b) —CF₃ —Cl B13 (a)and (b) —CF₃ —Br B14 (a) and (b) —CF₃ —I B15 (a) and (b) —CF₃ -n-butylB16 (a) and (b) —CF₃ -n-propyl B17 (a) and (b) —CF₃ -iso-propyl B18 (a)and (b) —CF₃ —C₆H₅ B19 (a) and (b) —CF₃ —H B20 (a) and (b) —NO₂-tert-butyl B21 (a) and (b) —NO₂ -iso-butyl B22 (a) and (b) —NO₂-sec-butyl B23 (a) and (b) —NO₂ -cyclohexyl B24 (a) and (b) —NO₂-tert-butoxy B25 (a) and (b) —NO₂ -iso-propoxy B26 (a) and (b) —NO₂ —CF₃B27 (a) and (b) —NO₂ —CH₃ B28 (a) and (b) —NO₂ —CH₂CF₃ B29 (a) and (b)—NO₂ —OCF₃ B30 (a) and (b) —NO₂ —OCH₃ B31 (a) and (b) —NO₂ —Cl B32 (a)and (b) —NO₂ —Br B33 (a) and (b) —NO₂ —I B34 (a) and (b) —NO₂ -n-butylB35 (a) and (b) —NO₂ -n-propyl B36 (a) and (b) —NO₂ -iso-propyl B37 (a)and (b) —NO₂ —C₆H₅ B38 (a) and (b) —NO₂ —H B39 (a) and (b) —CN-tert-butyl B40 (a) and (b) —CN -iso-butyl B41 (a) and (b) —CN-sec-butyl B42 (a) and (b) —CN -cyclohexyl B43 (a) and (b) —CN-tert-butoxy B44 (a) and (b) —CN -iso-propoxy B45 (a) and (b) —CN —CF₃B46 (a) and (b) —CN —CH₃ B47 (a) and (b) —CN —CH₂CF₃ B48 (a) and (b) —CN—OCF₃ B49 (a) and (b) —CN —OCH₃ B50 (a) and (b) —CN —Cl B51 (a) and (b)—CN —Br B52 (a) and (b) —CN —I B53 (a) and (b) —CN -n-butyl B54 (a) and(b) —CN -n-propyl B55 (a) and (b) —CN -iso-propyl B56 (a) and (b) —CN—C₆H₅ B57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

TABLE 3 (V)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ C1—CF₃ -tert-butyl C2 —CF₃ -iso-butyl C3 —CF₃ -sec-butyl C4 —CF₃-cyclohexyl C5 —CF₃ -tert-butoxy C6 —CF₃ -iso-propoxy C7 —CF₃ —CF₃ C8—CF₃ —CH₃ C9 —CF₃ —CH₂CF₃ C10 —CF₃ —OCF₃ C11 —CF₃ —OCH₃ C12 —CF₃ —Cl C13—CF₃ —Br C14 —CF₃ —I C15 —CF₃ -n-butyl C16 —CF₃ -n-propyl C17 —CF₃-iso-propyl C18 —CF₃ —C₆H₅ C19 —CF₃ —H C20 —NO₂ -tert-butyl C21 —NO₂-iso-butyl C22 —NO₂ -sec-butyl C23 —NO₂ -cyclohexyl C24 —NO₂-tert-butoxy C25 —NO₂ -iso-propoxy C26 —NO₂ —CF₃ C27 —NO₂ —CH₃ C28 —NO₂—CH₂CF₃ C29 —NO₂ —OCF₃ C30 —NO₂ —OCH₃ C31 —NO₂ —Cl C32 —NO₂ —Br C33 —NO₂—I C34 —NO₂ -n-butyl C35 —NO₂ -n-propyl C36 —NO₂ -iso-propyl C37 —NO₂—C₆H₅ C38 —NO₂ —H C39 —CN -tert-butyl C40 —CN -iso-butyl C41 —CN-sec-butyl C42 —CN -cyclohexyl C43 —CN -tert-butoxy C44 —CN -iso-propoxyC45 —CN —CF₃ C46 —CN —CH₃ C47 —CN —CH₂CF₃ C48 —CN —OCF₃ C49 —CN —OCH₃C50 —CN —Cl C51 —CN —Br C52 —CN —I C53 —CN -n-butyl C54 —CN -n-propylC55 —CN -iso-propyl C56 —CN —C₆H₅ C57 —CN —H

TABLE 4 (VI)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ D1(a) and (b) —CF₃ -tert-butyl D2 (a) and (b) —CF₃ -iso-butyl D3 (a) and(b) —CF₃ -sec-butyl D4 (a) and (b) —CF₃ -cyclohexyl D5 (a) and (b) —CF₃-tert-butoxy D6 (a) and (b) —CF₃ -iso-propoxy D7 (a) and (b) —CF₃ —CF₃D8 (a) and (b) —CF₃ —CH₃ D9 (a) and (b) —CF₃ —CH₂CF₃ D10 (a) and (b)—CF₃ —OCF₃ D11 (a) and (b) —CF₃ —OCH₃ D12 (a) and (b) —CF₃ —Cl D13 (a)and (b) —CF₃ —Br D14 (a) and (b) —CF₃ —I D15 (a) and (b) —CF₃ -n-butylD16 (a) and (b) —CF₃ -n-propyl D17 (a) and (b) —CF₃ -iso-propyl D18 (a)and (b) —CF₃ —C₆H₅ D19 (a) and (b) —CF₃ —H D20 (a) and (b) —NO₂-tert-butyl D21 (a) and (b) —NO₂ -iso-butyl D22 (a) and (b) —NO₂-sec-butyl D23 (a) and (b) —NO₂ -cyclohexyl D24 (a) and (b) —NO₂-tert-butoxy D25 (a) and (b) —NO₂ -iso-propoxy D26 (a) and (b) —NO₂ —CF₃D27 (a) and (b) —NO₂ —CH₃ D28 (a) and (b) —NO₂ —CH₂CF₃ D29 (a) and (b)—NO₂ —OCF₃ D30 (a) and (b) —NO₂ —OCH₃ D31 (a) and (b) —NO₂ —Cl D32 (a)and (b) —NO₂ —Br D33 (a) and (b) —NO₂ —I D34 (a) and (b) —NO₂ -n-butylD35 (a) and (b) —NO₂ -n-propyl D36 (a) and (b) —NO₂ -iso-propyl D37 (a)and (b) —NO₂ —C₆H₅ D38 (a) and (b) —NO₂ —H D39 (a) and (b) —CN-tert-butyl D40 (a) and (b) —CN -iso-butyl D41 (a) and (b) —CN-sec-butyl D42 (a) and (b) —CN -cyclohexyl D43 (a) and (b) —CN-tert-butoxy D44 (a) and (b) —CN -iso-propoxy D45 (a) and (b) —CN —CF₃D46 (a) and (b) —CN —CH₃ D47 (a) and (b) —CN —CH₂CF₃ D48 (a) and (b) —CN—OCF₃ D49 (a) and (b) —CN —OCH₃ D50 (a) and (b) —CN —Cl D51 (a) and (b)—CN —Br D52 (a) and (b) —CN —I D53 (a) and (b) —CN -n-butyl D54 (a) and(b) —CN -n-propyl D55 (a) and (b) —CN -iso-propyl D56 (a) and (b) —CN—C₆H₅ D57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

TABLE 5 (VII)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ E1—CF₃ -tert-butyl E2 —CF₃ -iso-butyl E3 —CF₃ -sec-butyl E4 —CF₃-cyclohexyl ES —CF₃ -tert-butoxy E6 —CF₃ -iso-propoxy E7 —CF₃ —CF₃ E8—CF₃ —CH₃ E9 —CF₃ —CH₂CF₃ E10 —CF₃ —OCF₃ E11 —CF₃ —OCH₃ E12 —CF₃ —Cl E13—CF₃ —Br E14 —CF₃ —I E15 —CF₃ -n-butyl E16 —CF₃ -n-propyl E17 —CF₃-iso-propyl E18 —CF₃ —C₆H₅ E19 —CF₃ —H E20 —NO₂ -tert-butyl E21 —NO₂-iso-butyl E22 —NO₂ -sec-butyl E23 —NO₂ -cyclohexyl E24 —NO₂-tert-butoxy E25 —NO₂ -iso-propoxy E26 —NO₂ —CF₃ E27 —NO₂ —CH₃ E28 —NO₂—CH₂CF₃ E29 —NO₂ —OCF₃ E30 —NO₂ —OCH₃ E31 —NO₂ —Cl E32 —NO₂ —Br E33 —NO₂—I E34 —NO₂ -n-butyl E35 —NO₂ -n-propyl E36 —NO₂ -iso-propyl E37 —NO₂—C₆H₅ E38 —NO₂ —H E39 —CN -tert-butyl E40 —CN -iso-butyl E41 —CN-sec-butyl E42 —CN -cyclohexyl E43 —CN -tert-butoxy E44 —CN -iso-propoxyE45 —CN —CF₃ E46 —CN —CH₃ E47 —CN —CH₂CF₃ E48 —CN —OCF₃ E49 —CN —OCH₃E50 —CN —Cl E51 —CN —Br E52 —CN —I E53 —CN -n-butyl E54 —CN -n-propylE55 —CN -iso-propyl E56 —CN —C₆H₅ E57 —CN —H

TABLE 6 (VIII)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ F1(a) and (b) —CF₃ -tert-butyl F2 (a) and (b) —CF₃ -iso-butyl F3 (a) and(b) —CF₃ -sec-butyl F4 (a) and (b) —CF₃ -cyclohexyl F5 (a) and (b) —CF₃-tert-butoxy F6 (a) and (b) —CF₃ -iso-propoxy F7 (a) and (b) —CF₃ —CF₃F8 (a) and (b) —CF₃ —CH₃ F9 (a) and (b) —CF₃ —CH₂CF₃ F10 (a) and (b)—CF₃ —OCF₃ F11 (a) and (b) —CF₃ —OCH₃ F12 (a) and (b) —CF₃ —Cl F13 (a)and (b) —CF₃ —Br F14 (a) and (b) —CF₃ —I F15 (a) and (b) —CF₃ -n-butylF16 (a) and (b) —CF₃ -n-propyl F17 (a) and (b) —CF₃ -iso-propyl F18 (a)and (b) —CF₃ —C₆H₅ F19 (a) and (b) —CF₃ —H F20 (a) and (b) —NO₂-tert-butyl F21 (a) and (b) —NO₂ -iso-butyl F22 (a) and (b) —NO₂-sec-butyl F23 (a) and (b) —NO₂ -cyclohexyl F24 (a) and (b) —NO₂-tert-butoxy F25 (a) and (b) —NO₂ -iso-propoxy F26 (a) and (b) —NO₂ —CF₃F27 (a) and (b) —NO₂ —CH₃ F28 (a) and (b) —NO₂ —CH₂CF₃ F29 (a) and (b)—NO₂ —OCF₃ F30 (a) and (b) —NO₂ —OCH₃ F31 (a) and (b) —NO₂ —Cl F32 (a)and (b) —NO₂ —Br F33 (a) and (b) —NO₂ —I F34 (a) and (b) —NO₂ -n-butylF35 (a) and (b) —NO₂ -n-propyl F36 (a) and (b) —NO₂ -iso-propyl F37 (a)and (b) —NO₂ —C₆H₅ F38 (a) and (b) —NO₂ —H F39 (a) and (b) —CN-tert-butyl F40 (a) and (b) —CN -iso-butyl F41 (a) and (b) —CN-sec-butyl F42 (a) and (b) —CN -cyclohexyl F43 (a) and (b) —CN-tert-butoxy F44 (a) and (b) —CN -iso-propoxy F45 (a) and (b) —CN —CF₃F46 (a) and (b) —CN —CH₃ F47 (a) and (b) —CN —CH₂CF₃ F48 (a) and (b) —CN—OCF₃ F49 (a) and (b) —CN —OCH₃ F50 (a) and (b) —CN —Cl F51 (a) and (b)—CN —Br F52 (a) and (b) —CN —I F53 (a) and (b) —CN -n-butyl F54 (a) and(b) —CN -n-propyl F55 (a) and (b) —CN -iso-propyl F56 (a) and (b) —CN—C₆H₅ F57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

TABLE 7 (IX)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ G1—CF₃ -tert-butyl G2 —CF₃ -iso-butyl G3 —CF₃ -sec-butyl G4 —CF₃-cyclohexyl G5 —CF₃ -tert-butoxy G6 —CF₃ -iso-propoxy G7 —CF₃ —CF₃ G8—CF₃ —CH₃ G9 —CF₃ —CH₂CF₃ G10 —CF₃ —OCF₃ G11 —CF₃ —OCH₃ G12 —CF₃ —Cl G13—CF₃ —Br G14 —CF₃ —I G15 —CF₃ -n-butyl G16 —CF₃ -n-propyl G17 —CF₃-iso-propyl G18 —CF₃ —C₆H₅ G19 —CF₃ —H G20 —NO₂ -tert-butyl G21 —NO₂-iso-butyl G22 —NO₂ -sec-butyl G23 —NO₂ -cyclohexyl G24 —NO₂-tert-butoxy G25 —NO₂ -iso-propoxy G26 —NO₂ —CF₃ G27 —NO₂ —CH₃ G28 —NO₂—CH₂CF₃ G29 —NO₂ —OCF₃ G30 —NO₂ —OCH₃ G31 —NO₂ —Cl G32 —NO₂ —Br G33 —NO₂-I G34 —NO₂ -n-butyl G35 —NO₂ -n-propyl G36 —NO₂ -iso-propyl G37 —NO₂—C₆H₅ G38 —NO₂ —H G39 —CN -tert-butyl G40 —CN -iso-butyl G41 —CN-sec-butyl G42 —CN -cyclohexyl G43 —CN -tert-butoxy G44 —CN -iso-propoxyG45 —CN —CF₃ G46 —CN —CH₃ G47 —CN —CH₂CF₃ G48 —CN —OCF₃ G49 —CN —OCH₃G50 —CN —Cl G51 —CN —Br G52 —CN —I 053 —CN -n-butyl G54 —CN -n-propylG55 —CN -iso-propyl G56 —CN —C₆H₅ G57 —CN —H

TABLE 8 (X)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ H1(a) and (b) —CF₃ -tert-butyl H2 (a) and (b) —CF₃ -iso-butyl H3 (a) and(b) —CF₃ -sec-butyl H4 (a) and (b) —CF₃ -cyclohexyl H5 (a) and (b) —CF₃-tert-butoxy H6 (a) and (b) —CF₃ -iso-propoxy H7 (a) and (b) —CF₃ —CF₃H8 (a) and (b) —CF₃ —CH₃ H9 (a) and (b) —CF₃ —CH₂CF₃ H10 (a) and (b)—CF₃ —OCF₃ H11 (a) and (b) —CF₃ —OCH₃ H12 (a) and (b) —CF₃ —Cl H13 (a)and (b) —CF₃ —Br H14 (a) and (b) —CF₃ —I H15 (a) and (b) —CF₃ -n-butylH16 (a) and (b) —CF₃ -n-propyl H17 (a) and (b) —CF₃ -iso-propyl H18 (a)and (b) —CF₃ —C₆H₅ H19 (a) and (b) —CF₃ —H H20 (a) and (b) —NO₂-tert-butyl H21 (a) and (b) —NO₂ -iso-butyl H22 (a) and (b) —NO₂-sec-butyl H23 (a) and (b) —NO₂ -cyclohexyl H24 (a) and (b) —NO₂-tert-butoxy H25 (a) and (b) —NO₂ -iso-propoxy H26 (a) and (b) —NO₂ —CF₃H27 (a) and (b) —NO₂ —CH₃ H28 (a) and (b) —NO₂ —CH₂CF₃ H29 (a) and (b)—NO₂ —OCF₃ H30 (a) and (b) —NO₂ —OCH₃ H31 (a) and (b) —NO₂ —Cl H32 (a)and (b) —NO₂ —Br H33 (a) and (b) —NO₂ —I H34 (a) and (b) —NO₂ -n-butylH35 (a) and (b) —NO₂ -n-propyl H36 (a) and (b) —NO₂ -iso-propyl H37 (a)and (b) —NO₂ —C₆H₅ H38 (a) and (b) —NO₂ —H H39 (a) and (b) —CN-tert-butyl H40 (a) and (b) —CN -iso-butyl H41 (a) and (b) —CN-sec-butyl H42 (a) and (b) —CN -cyclohexyl H43 (a) and (b) —CN-tert-butoxy H44 (a) and (b) —CN -iso-propoxy H45 (a) and (b) —CN —CF₃H46 (a) and (b) —CN —CH₃ H47 (a) and (b) —CN —CH₂CF₃ H48 (a) and (b) —CN—OCF₃ H49 (a) and (b) —CN —OCH₃ H50 (a) and (b) —CN —Cl H51 (a) and (b)—CN —Br H52 (a) and (b) —CN —I H53 (a) and (b) —CN -n-butyl H54 (a) and(b) —CN -n-propyl H55 (a) and (b) —CN -iso-propyl H56 (a) and (b) —CN—C₆H₅ H57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

TABLE 9 (XI)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ I1—CF₃ -tert-butyl I2 —CF₃ -iso-butyl I3 —CF₃ -sec-butyl I4 —CF₃-cyclohexyl I5 —CF₃ -tert-butoxy I6 —CF₃ -iso-propoxy I7 —CF₃ —CF₃ I8—CF₃ —CH₃ I9 —CF₃ —CH₂CF₃ I10 —CF₃ —OCF₃ I11 —CF₃ —OCH₃ I12 —CF₃ —Cl I13—CF₃ —Br I14 —CF₃ —I I15 —CF₃ -n-butyl I16 —CF₃ -n-propyl I17 —CF₃-iso-propyl I18 —CF₃ —C₆H₅ I19 —CF₃ —H I20 —NO₂ -tert-butyl I21 —NO₂-iso-butyl I22 —NO₂ -sec-butyl I23 —NO₂ -cyclohexyl I24 —NO₂-tert-butoxy I25 —NO₂ -iso-propoxy I26 —NO₂ —CF₃ I27 —NO₂ —CH₃ I28 —NO₂—CH₂CF₃ I29 —NO₂ —OCF₃ I30 —NO₂ —OCH₃ I31 —NO₂ —Cl I32 —NO₂ —Br I33 —NO₂—I I34 —NO₂ -n-butyl I35 —NO₂ -n-propyl I36 —NO₂ -iso-propyl I37 —NO₂—C₆H₅ I38 —NO₂ —H I39 —CN -tert-butyl I40 —CN -iso-butyl I41 —CN-sec-butyl I42 —CN -cyclohexyl I43 —CN -tert-butoxy I44 —CN -iso-propoxyI45 —CN —CF₃ I46 —CN —CH₃ I47 —CN —CH₂CF₃ I48 —CN —OCF₃ I49 —CN —OCH₃I50 —CN —Cl I51 —CN —Br I52 —CN —I I53 —CN -n-butyl I54 —CN -n-propylI55 —CN -iso-propyl I56 —CN —C₆H₅ I57 —CN —H

TABLE 10 (XII)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ J1(a) and (b) —CF₃ -tert-butyl J2 (a) and (b) —CF₃ -iso-butyl J3 (a) and(b) —CF₃ -sec-butyl J4 (a) and (b) —CF₃ -cyclohexyl J5 (a) and (b) —CF₃-tert-butoxy J6 (a) and (b) —CF₃ -iso-propoxy J7 (a) and (b) —CF₃ —CF₃J8 (a) and (b) —CF₃ —CH₃ J9 (a) and (b) —CF₃ —CH₂CF₃ J10 (a) and (b)—CF₃ —OCF₃ J11 (a) and (b) —CF₃ —OCH₃ J12 (a) and (b) —CF₃ —Cl J13 (a)and (b) —CF₃ —Br J14 (a) and (b) —CF₃ —I J15 (a) and (b) —CF₃ -n-butylJ16 (a) and (b) —CF₃ -n-propyl J17 (a) and (b) —CF₃ -iso-propyl J18 (a)and (b) —CF₃ —C₆H₅ J19 (a) and (b) —CF₃ —H J20 (a) and (b) —NO₂-tert-butyl J21 (a) and (b) —NO₂ -iso-butyl J22 (a) and (b) —NO₂-sec-butyl J23 (a) and (b) —NO₂ -cyclohexyl J24 (a) and (b) —NO₂-tert-butoxy J25 (a) and (b) —NO₂ -iso-propoxy J26 (a) and (b) —NO₂ —CF₃J27 (a) and (b) —NO₂ —CH₃ J28 (a) and (b) —NO₂ —CH₂CF₃ J29 (a) and (b)—NO₂ —OCF₃ J30 (a) and (b) —NO₂ —OCH₃ J31 (a) and (b) —NO₂ —Cl J32 (a)and (b) —NO₂ —Br J33 (a) and (b) —NO₂ —I J34 (a) and (b) —NO₂ -n-butylJ35 (a) and (b) —NO₂ -n-propyl J36 (a) and (b) —NO₂ -iso-propyl J37 (a)and (b) —NO₂ —C₆H₅ J38 (a) and (b) —NO₂ —H J39 (a) and (b) —CN-tert-butyl J40 (a) and (b) —CN -iso-butyl J41 (a) and (b) —CN-sec-butyl J42 (a) and (b) —CN -cyclohexyl J43 (a) and (b) —CN-tert-butoxy J44 (a) and (b) —CN -iso-propoxy J45 (a) and (b) —CN —CF₃J46 (a) and (b) —CN —CH₃ J47 (a) and (b) —CN —CH₂CF₃ J48 (a) and (b) —CN—OCF₃ J49 (a) and (b) —CN —OCH₃ J50 (a) and (b) —CN —Cl J51 (a) and (b)—CN —Br J52 (a) and (b) —CN —I J53 (a) and (b) —CN -n-butyl J54 (a) and(b) —CN -n-propyl J55 (a) and (b) —CN -iso-propyl J56 (a) and (b) —CN—C₆H₅ J57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

TABLE 11 (XIII)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ K1—CF₃ -tert-butyl K2 —CF₃ -iso-butyl K3 —CF₃ -sec-butyl K4 —CF₃-cyclohexyl K5 —CF₃ -tert-butoxy K6 —CF₃ -iso-propoxy K7 —CF₃ —CF₃ K8—CF₃ —CH₃ K9 —CF₃ —CH₂CF₃ K10 —CF₃ —OCF₃ K11 —CF₃ —OCH₃ K12 —CF₃ —Cl K13—CF₃ —Br K14 —CF₃ —I K15 —CF₃ -n-butyl K16 —CF₃ -n-propyl K17 —CF₃-iso-propyl K18 —CF₃ —C₆H₅ K19 —CF₃ —H K20 —NO₂ -tert-butyl K21 —NO₂-iso-butyl K22 —NO₂ -sec-butyl K23 —NO₂ -cyclohexyl K24 —NO₂-tert-butoxy K25 —NO₂ -iso-propoxy K26 —NO₂ —CF₃ K27 —NO₂ —CH₃ K28 —NO₂—CH₂CF₃ K29 —NO₂ —OCF₃ K30 —NO₂ —OCH₃ K31 —NO₂ —Cl K32 —NO₂ —Br K33 —NO₂—I K34 —NO₂ -n-butyl K35 —NO₂ -n-propyl K36 —NO₂ -iso-propyl K37 —NO₂—C₆H₅ K38 —NO₂ —H K39 —CN -tert-butyl K40 —CN -iso-butyl K41 —CN-sec-butyl K42 —CN -cyclohexyl K43 —CN -tert-butoxy K44 —CN -iso-propoxyK45 —CN —CF₃ K46 —CN —CH₃ K47 —CN —CH₂CF₃ K48 —CN —OCF₃ K49 —CN —OCH₃K50 —CN —Cl K51 —CN —Br K52 —CN —I K53 —CN -n-butyl K54 —CN -n-propylK55 —CN -iso-propyl K56 —CN —C₆H₅ K57 —CN —H

TABLE 12 (XIV)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₉ L1(a) and (b) —CF₃ -tert-butyl L2 (a) and (b) —CF₃ -iso-butyl L3 (a) and(b) —CF₃ -sec-butyl L4 (a) and (b) —CF₃ -cyclohexyl L5 (a) and (b) —CF₃-tert-butoxy L6 (a) and (b) —CF₃ -iso-propoxy L7 (a) and (b) —CF₃ —CF₃L8 (a) and (b) —CF₃ —CH₃ L9 (a) and (b) —CF₃ —CH₂CF₃ L10 (a) and (b)—CF₃ —OCF₃ L11 (a) and (b) —CF₃ —OCH₃ L12 (a) and (b) —CF₃ —Cl L13 (a)and (b) —CF₃ —Br L14 (a) and (b) —CF₃ —I L15 (a) and (b) —CF₃ -n-butylL16 (a) and (b) —CF₃ -n-propyl L17 (a) and (b) —CF₃ -iso-propyl- L18 (a)and (b) —CF₃ —C₆H₅ L19 (a) and (b) —CF₃ —H L20 (a) and (b) —NO₂-tert-butyl L21 (a) and (b) —NO₂ -iso-butyl L22 (a) and (b) —NO₂-sec-butyl L23 (a) and (b) —NO₂ -cyclohexyl L24 (a) and (b) —NO₂-tert-butoxy L25 (a) and (b) —NO₂ -iso-propoxy L26 (a) and (b) —NO₂ —CF₃L27 (a) and (b) —NO₂ —CH₃ L28 (a) and (b) —NO₂ —CH₂CF₃ L29 (a) and (b)—NO₂ —OCF₃ L30 (a) and (b) —NO₂ —OCH₃ L31 (a) and (b) —NO₂ —Cl L32 (a)and (b) —NO₂ —Br L33 (a) and (b) —NO₂ —I L34 (a) and (b) —NO₂ -n-butylL35 (a) and (b) —NO₂ -n-propyl L36 (a) and (b) —NO₂ -iso-propyl L37 (a)and (b) —NO₂ —C₆H₅ L38 (a) and (b) —NO₂ —H L39 (a) and (b) —CN-tert-butyl L40 (a) and (b) —CN -iso-butyl L41 (a) and (b) —CN-sec-butyl L42 (a) and (b) —CN -cyclohexyl L43 (a) and (b) —CN-tert-butoxy L44 (a) and (b) —CN -iso-propoxy L45 (a) and (b) —CN —CF₃L46 (a) and (b) —CN —CH₃ L47 (a) and (b) —CN —CH₂CF₃ L48 (a) and (b) —CN—OCF₃ L49 (a) and (b) —CN —OCH₃ L50 (a) and (b) —CN —Cl L51 (a) and (b)—CN —Br L52 (a) and (b) —CN —I L53 (a) and (b) —CN -n-butyl L54 (a) and(b) —CN -n-propyl L55 (a) and (b) —CN -iso-propyl L56 (a) and (b) —CN—C₆H₅ L57 (a) and (b) —CN —Hwhere “(a)” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration, and “(b)” meansthat the carbon atom of the piperazino group to which the methyl groupis attached is in the S configuration.

4.4 Definitions

As used herein, the terms used above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include

-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl,-n-octyl, -n-nonyl and -n-decyl. Representative branched —(C₁-C₁₀)alkylsinclude -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbutyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and-cyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₈-C₁₄)bicycloalkyls include -indanyl,-1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl,-perhydronaphthyl and the like.

“-(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated ring.Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl,-1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthreneyl,-1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl,-perhydrophenanthrenyl and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.

“-(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“-(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls include-indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,-1,2,7,8-tetrahydronaphthalenyl and the like.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl and the like.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, a 5-membered heterocyclecan contain up to 4 heteroatoms, a 6-membered heterocycle can contain upto 6 heteroatoms, and a 7-membered heterocycle can contain up to 7heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 7-membered)heterocycle can be attached via anitrogen, sulfur, or carbon atom. Representative -(3- to7-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl,oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl,hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, and a 5-memberedheterocycle can contain up to 4 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(3- to5-membered)heterocycle can be attached via a nitrogen, sulfur, or carbonatom. Representative -(3- to 5-membered)heterocycles include furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyland the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen,sulfur, or carbon atom. Representative -(7- to10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl,-chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl,-benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl,-isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl,-β-carbolinyl and the like.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen and sulfur. Inone embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl,phthalazinyl, and quinazolinyl.

“-Halogen” or “-halo” means —F, —Cl, —Br or —I.

The phrase “pyridyl group” means

where R₁, R₂, and n are defined above for the 3-substituted PyridylCompounds of formulas (I) and (II).

The phrase “phenethyl group” means an ethylene group attached to aterminal Ar₂ group, where one or each of two hydrogens of the ethylenegroup can optionally be substituted with an R₈ group. A phenethyl groupis depicted below:

where R₈ Ar₂, and t are defined above for the 3-substituted PyridylCompounds of formulas (I).

The phrase “phenpropyl group” an n-propylene group attached to aterminal Ar₂ group, where one or each of two hydrogens of then-propylene group can optionally be substituted with an R₈ group. Aphenpropyl group is depicted below

where R₈, Ar₂, and t are defined above for the 3-substituted PyridylCompounds of formulas (II).

The phrase “effective amount,” when used in connection with a3-substituted Pyridyl Compound means an amount effective for: (a)treating or preventing a Condition; or (b) inhibiting VR1, mGluR1, ormGluR5 function in a cell.

The phrase “effective amount,” when used in connection with the anothertherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

The term “animal,” includes, but is not limited to, a cow, monkey,chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig and human.

The phrase “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from a3-substituted Pyridyl Compound, including a salt formed from an acid anda basic functional group, such as a nitrogen group, of one of the3-substituted Pyridyl Compounds. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from a3-substituted Pyridyl Compound having an acidic functional group, suchas a carboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

When a first group is “substituted with one or more” second groups, eachof one or more of the first group's hydrogen atoms is replaced with asecond group.

In one embodiment, each carbon atom of a first group is independentlysubstituted with one or two second groups. In another embodiment, eachcarbon atom of a first group is independently substituted with only onesecond group.

The term “UI” means urinary incontinence.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The term “DMSO” means dimethyl sulfoxide.

The term “DMF” means dimethyl formamide.

The term “DCM” means dichloromethane.

The term “DIEA” means diisopropylethylamine.

The phrases “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasingthe overall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof.

4.5 Methods for Making the 3-Substituted Pyridyl Compounds

The 3-substituted Pyridyl Compounds can be made using conventionalorganic synthesis or by the following illustrative methods shown in theschemes below.

The 3-substituted Pyridyl Compounds of Formula (I) and (II) can beobtained using conventional organic syntheses or by the followingillustrative methods shown in below in Scheme 1.

where Ar₂, R₁, R₂, R₃, R₈, n, m, and t are as defined above.

Compound A is reacted with an isocyanate or isothiocyanate of formula Aor B in a suitable solvent, preferably DCM, at a suitable temperature,preferably at about 25° C., to provide the 3-substituted PyridylCompound where X═O and X═S, respectively.

If the 3-substituted Pyridyl Compound is substituted with a hydroxylgroup or thiol group, then the hydroxyl or thiol group of compound A ispreferably protected with a suitable protecting group before beingreacted with the isocyanate or isothiocyanate. Suitable protectinggroups for hydroxyl group include, but are not limited to, methyl ether,methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethylether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether,tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether,methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether,tetrahydrothiofuranyl ether, 1-ethoxyethyl ether,1-methyl-1-methoxyethyl ether, 2-(phenylselenyl ether), tert-butylether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethylether, o-napthyldiphenylmethyl ether, p-methoxydiphenylmethyl ether,9-(9-phenyl-10-oxo)anthryl ether (tritylone), trimethylsilyl ether,isopropyldimethylsilyl ether, tert-butyldimethylsilyl ether,tert-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilylether, formate ester, acetate ester, trichloroacetate ester,phenoxyacetate ester, isobutyrate ester, pivaloate ester, adamantoateester, benzoate ester, 2,4,6-trimethyl (mesitoate) ester, methylcarbonate, 2,2,2-trichlorocarbonate, allyl carbonate, p-nitrophenylcarbonate, benzyl carbonate, p-nitrobenzyl carbonate,S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and2,4-dinitrophenylsulfenate ester (See, e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis 10-72 (1981)).

Suitable protecting groups for a thiol group include, but are notlimited to, S-benzyl thioether, S-p-methoxybenzyl thioether,S-p-nitrobenzyl thioether, S-4-picolyl thioether, S-2-picolyl N-oxidethioether, S-9-anthrylmethyl thioether, S-diphenylmethyl thioether,S-di(p-methoxyphenyl)methyl thioether, S-triphenylmethyl thioether,S-2,4-dinitrophenyl thioether, S-tert-butyl thioether,S-iso-butoxymethyl hemithioacetal, S-2-tetrahydropyranyl hemithioacetal,S-acetamidomethyl aminothioacetal, S-cyanomethyl thioether,S-2-nitro-1-phenylethyl thioether, S-2,2-bis(carboethoxy)ethylthioether, S-benzoyl derivative, S—(N-ethylcarbamate), andS-ethyldisulfide. Id. at 193-217.

The compound of formula A can be prepared by reacting a3-halo-substituted pyridine of formula D with a piperazine E inchloroform, in the presence of triethylamine at a temperature of about50° C. as shown below in Scheme 2.

where R₁, R₂, R₃, R₈, n, and m are defined above and Q is I, Br, Cl, orF.

A representative procedure for reacting a 3-halo-pyridines withpiperazine is provided in E. J. Jacobsen et al., J. Med. Chem. 1145-1151(1990).

The substituted 3-halo-pyridines D are commercially available or can beprepared by methods known to those skilled in the art.

Isocyanates B and C are commercially available or preparable by reactingan amine of formula F or G, shown below,

with phosgene according to well-known methods (See, e.g., H. Eckert etal., Angew. Chem. Int. Ed Engl. 26:894 (1987); H. Eckert, Ger. Offen. DE3 440 141; Chem. Abstr. 106:4294d (1987); and L. Contarca et al.,Synthesis 553-576 (1996)).

Typically, a solution of triphosgene (0.3 eq) in 1,2-dichloroethane (0.3M) is slowly added to a stirred solution of the amine (1.0 eq.) in1,2-dichloroethane (0.3 M) at about 25° C. The reaction mixture is thenstirred at about 25° C. for about 10 min. and the temperature thenraised to about 70° C. After stirring at about 70° C. for about 3 h, thereaction mixture is cooled to about 25° C., filtered, and the filtrateconcentrated to give the desired isocyanate.

Isothiocyanates B and C are commercially available or preparable byreacting an amine of formula F or G with thiophosgene (See, e.g.,Tetrahedron Lett., 41 (37):7207-7209 (2000); Synlett 11:1784-1786(1999); Heterocycles 32:2343-2355 (1991); Org. Prep., Proced., Int. 23(6):729-734 (1991); J. Heterocycle Chem. 28 (4):1091-1097 (1991); J.Fluorine Chem. 41 (3):303-310 (1988); J. Med. Chem. 32 (6):1173-1176 and1392-1398 (1989); and Tetrahedron Lett. 42 (32):5414-5416 (2001).

Alternatively, isothiocyanates B and C can be prepared by reacting anamine of formula F or G with carbon disulfide in the presence oftriethylamine in tetrahydrofuran, followed by reaction with hydrogenperoxide and hydrochloric acid in water (See, e.g., J. Org. Chem., 62(13), 4539-4540 (1997)).

The 3-substituted Pyridyl Compounds of Formula (I) and (II) where X is Ocan also be prepared by reacting an amine of formula F or G with4-nitrophenylchloroformate (commercially available from Sigma-Aldrich,St. Louis, Mo. (www.sigma-aldrich.com)) to provide a carbamate, CompoundH or I, and then reacting Compound H or I with Compound A as shown belowin Schemes 3 and 4 (See, e.g., J. Org. Chem. 63 (23):8515-8521 (1998)and European Patent Publication No. 549 039).

where R₁, R₂, R₃, n, and m are defined above for the Pyridyl Compoundsof Formula (I) and (II).

4.6 Therapeutic Uses of the Pyradizinylpiperazine Compounds

In accordance with the invention, the 3-substituted Pyridyl Compoundsare administered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a 3-substituted PyridylCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting VR1. Examples of conditions that are treatableor preventable by inhibiting VR1 include, but are not limited to, pain,UI, an ulcer, IBD, and IBS.

In another embodiment, an effective amount of a 3-substituted PyridylCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR5. Examples of conditions that aretreatable or preventable by inhibiting mGluR5 include, but are notlimited to, pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, and psychosis.

In another embodiment, an effective amount of a 3-substituted PyridylCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR1. Examples of conditions that aretreatable or preventable by inhibiting mGluR1 include, but are notlimited to, pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, and depression.

The 3-substituted Pyridyl Compounds can be used to treat or preventacute or chronic pain. Examples of pain treatable or preventable usingthe 3-substituted Pyridyl Compounds include, but are not limited to,cancer pain, labor pain, myocardial infarction pain, pancreatic pain,colic pain, post-operative pain, headache pain, muscle pain, arthriticpain, and pain associated with a periodontal disease, includinggingivitis and periodontitis.

The 3-substituted Pyridyl Compounds can also be used for treating orpreventing pain associated with inflammation or with an inflammatorydisease in an animal. Such pain can arise where there is an inflammationof the body tissue which can be a local inflammatory response and/or asystemic inflammation. For example, the 3-substituted Pyridyl Compoundscan be used to treat or prevent pain associated with inflammatorydiseases including, but not limited to: organ transplant rejection;reoxygenation injury resulting from organ transplantation (see Grupp etal., J. Mol, Cell Cardiol. 31:297-303 (1999)) including, but not limitedto, transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis;uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disease of the gum, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney, includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisease of the skin, including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune diseases, including Type I and Type II diabetesmellitus; diabetic complications, including, but not limited to,diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), polyneuropathy,mononeuropathies, autonomic neuropathy, gangrene of the feet,atherosclerotic coronary arterial disease, peripheral arterial disease,nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems,and a skin or mucous membrane complication (such as an infection, a shinspot, a candidal infection or necrobiosis lipoidica diabeticorum);immune-complex vasculitis, and systemic lupus erythematosus (SLE);inflammatory disease of the heart, such as cardiomyopathy, ischemicheart disease hypercholesterolemia, and artherosclerosis; as well asvarious other diseases that can have significant inflammatorycomponents, including preeclampsia, chronic liver failure, brain andspinal cord trauma, and cancer. The 3-substituted Pyridyl Compounds canalso be used for inhibiting, treating, or preventing pain associatedwith inflammatory disease that can, for example, be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer.

The 3-substituted Pyridyl Compounds can be used to treat or prevent UI.Examples of UI treatable or preventable using the 3-substituted PyridylCompounds include, but are not limited to, urge incontinence, stressincontinence, overflow incontinence, neurogenic incontinence, and totalincontinence.

The 3-substituted Pyridyl Compounds can be used to treat or prevent anulcer. Examples of ulcers treatable or preventable using the3-substituted Pyridyl Compounds include, but are not limited to, aduodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer,or a stress ulcer.

The 3-substituted Pyridyl Compounds can be used to treat or prevent IBD,including Crohn's disease and ulcerative colitis.

The 3-substituted Pyridyl Compounds can be used to treat or prevent IBS.Examples of IBS treatable or preventable using the 3-substituted PyridylCompounds include, but are not limited to, spastic-colon-type IBS andconstipation-predominant IBS.

The 3-substituted Pyridyl Compounds can be used to treat or prevent anaddictive disorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and EatingDisorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to, AlcoholInduced Psychotic Disorder with delusions, Alcohol Abuse, AlcoholIntoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, AlcoholWithdrawal Delirium, Alcohol Induced Persisting Dementia, AlcoholInduced Persisting Amnestic Disorder, Alcohol Dependence, AlcoholInduced Psychotic Disorder with hallucinations, Alcohol Induced MoodDisorder, Alcohol Induced Anxiety Disorder, Alcohol Induced SexualDysfunction, Alcohol Induced Sleep Disorder, and Alcohol RelatedDisorder not otherwise specified (NOS).

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium, AmphetamineInduced Psychotic Disorder with delusions, Amphetamine Induced PsychoticDisorders with hallucinations, Amphetamine Induced Mood Disorder,Amphetamine Induced Anxiety Disorder, Amphetamine Induced SexualDysfunction, Amphetamine Induced Sleep Disorder, and Amphetamine RelatedDisorder not otherwise specified (NOS).

Cannabis-related disorders include, but are not limited to, CannabisDependence, Cannabis Abuse, Cannabis Intoxication, Cannabis IntoxicationDelirium, Cannabis Induced Psychotic Disorder with delusions, CannabisInduced Psychotic Disorder with hallucinations, Cannabis Induced AnxietyDisorder, and Cannabis Related Disorder not otherwise specified (NOS).

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine Induced Psychotic Disorder withdelusions, Cocaine Induced Psychotic Disorders with hallucinations,Cocaine Induced Mood Disorder, Cocaine Induced Anxiety Disorder, CocaineInduced Sexual Dysfunction, Cocaine Induced Sleep Disorder, and CocaineRelated Disorder not otherwise specified (NOS).

Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen Persisting Perception Disorder (Flashbacks), HallucinogenInduced Psychotic Disorder with delusions, Hallucinogen InducedPsychotic Disorders with hallucinations, Hallucinogen Induced MoodDisorder, Hallucinogen Induced Anxiety Disorder, Hallucinogen InducedSexual Dysfunction, Hallucinogen Induced Sleep Disorder, andHallucinogen Related Disorder not otherwise specified (NOS).

Inhalant-related disorders include, but are not limited to, InhalantDependence, Inhalant Abuse, Inhalant Intoxication, Inhalant IntoxicationDelirium, Inhalant Induced Psychotic Disorder with delusions, InhalantInduced Psychotic Disorder with hallucinations, Inhalant Induced AnxietyDisorder, and Inhalant Related Disorder not otherwise specified (NOS).

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, OpioidIntoxication Delirium, Opioid Induced Psychotic Disorder with delusions,Opioid Induced Psychotic Disorder with hallucinations, Opioid InducedAnxiety Disorder, and Opioid Related Disorder not otherwise specified(NOS).

The 3-substituted Pyridyl Compounds can be used to treat or preventParkinson's disease and parkinsonism and the symptoms associated withParkinson's disease and parkinsonism, including but not limited to,bradykinesia, muscular rigidity, resting tremor, and impairment ofpostural balance.

The 3-substituted Pyridyl Compounds can be used to treat or preventgeneralized anxiety or severe anxiety and the symptoms associated withanxiety, including but not limited to, restlessness; tension;tachycardia; dyspnea; depression, including chronic “neurotic”depression; panic disorder; agoraphobia and other specific phobias;eating disorders; and personality disorders.

The 3-substituted Pyridyl Compounds can be used to treat or preventepilepsy, including but not limited to, partial epilepsy, generalizedepilepsy, and the symptoms associated with epilepsy, including but notlimited to, simple partial seizures, jacksonian seizures, complexpartial (psychomotor) seizures, convulsive seizures (grand mal ortonic-clonic seizures), petit mal (absence) seizures, and statusepilepticus.

The 3-substituted Pyridyl Compounds can be used to treat or prevent astroke, including but not limited to, an ischemic stroke and ahemorrhagic stroke.

The 3-substituted Pyridyl Compounds can be used to treat or prevent aseizure, including but not limited to, infantile spasms, febrileseizures, and epileptic seizures.

The 3-substituted Pyridyl Compounds can be used to treat or prevent apruritic condition, including but not limited to, pruritus caused by dryskin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritusvulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis,drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The 3-substituted Pyridyl Compounds can be used to treat or preventpsychosis, including but not limited to, schizophrenia, includingparanoid schizophrenia, hebephrenic or disorganized schizophrenia,catatonic schizophrenia, undifferentiated schizophrenia, negative ordeficit subtype schizophrenia, and non-deficit schizophrenia; adelusional disorder, including erotomanic subtype delusional disorder,grandiose subtype delusional disorder, jealous subtype delusionaldisorder, persecutory subtype delusional disorder, and somatic subtypedelusional disorder; and brief psychosis.

The 3-substituted Pyridyl Compounds can be used to treat or prevent acognitive disorder, including but not limited to, delirium and dementiasuch as multi-infarct dementia, dementia pugilistica, dementia caused byAIDS, and dementia caused by Alzheimer's disease.

The 3-substituted Pyridyl Compounds can be used to treat or prevent amemory deficiency, including but not limited to, dissociative amnesiaand dissociative fugue.

The 3-substituted Pyridyl Compounds can be used to treat or preventrestricted brain function, including but not limited to, that caused bysurgery or an organ transplant, restricted blood supply to the brain, aspinal cord injury, a head injury, hypoxia, cardiac arrest, orhypoglycemia.

The 3-substituted Pyridyl Compounds can be used to treat or preventHuntington's chorea.

The 3-substituted Pyridyl Compounds can be used to treat or prevent ALS.

The 3-substituted Pyridyl Compounds can be used to treat or preventretinopathy, including but not limited to, arteriosclerotic retinopathy,diabetic arteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

The 3-substituted Pyridyl Compounds can be used to treat or prevent amuscle spasm.

The 3-substituted Pyridyl Compounds can be used to treat or prevent amigraine.

The 3-substituted Pyridyl Compounds can be used to treat, inhibit, orprevent vomiting, including but not limited to, nausea vomiting, dryvomiting (retching), and regurgitation.

The 3-substituted Pyridyl Compounds can be used to treat or preventdyskinesia, including but not limited to, tardive dyskinesia and biliarydyskinesia.

The 3-substituted Pyridyl Compounds can be used to treat or preventdepression, including but not limited to, major depression and bipolardisorder.

Applicants believe that the 3-substituted Pyridyl Compounds areantagonists for VR1.

The invention also relates to methods for inhibiting VR1 function in acell, comprising contacting a cell capable of expressing VR1 with aneffective amount of a 3-substituted Pyridyl Compound. This method can beused in vitro, for example, as an assay to select cells that express VR1and, accordingly, are useful as part of an assay to select compoundsuseful for treating or preventing pain, UI, an ulcer, IBD, or IBS. Themethod is also useful for inhibiting VR1 function in a cell in vivo, inan animal, a human in one embodiment, by contacting a cell, in ananimal, with an effective amount of a 3-substituted Pyridyl Compound. Inone embodiment, the method is useful for treating or preventing pain inan animal. In another embodiment, the method is useful for treating orpreventing UI in an animal. In another embodiment, the method is usefulfor treating or preventing an ulcer in an animal. In another embodiment,the method is useful for treating or preventing IBD in an animal. Inanother embodiment, the method is useful for treating or preventing IBSin an animal.

Examples of tissue comprising cells capable of expressing VR1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express VR1 are known in theart.

Applicants believe that the 3-substituted Pyridyl Compounds areantagonists for mGluR5.

The invention also relates to methods for inhibiting mGluR5 function ina cell, comprising contacting a cell capable of expressing mGluR5 withan amount of a 3-substituted Pyridyl Compound effective to inhibitmGluR5 function in the cell. This method can be used in vitro, forexample, as an assay to select cells that express mGluR5 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, a pruritic condition, or psychosis. Themethod is also useful for inhibiting mGluR5 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an amount of a 3-substituted Pyridyl Compound effective toinhibit mGluR5 function in the cell. In one embodiment, the method isuseful for treating or preventing pain in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing anaddictive disorder in an animal in need thereof. In another embodiment,the method is useful for treating or preventing Parkinson's disease inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing parkinsonism in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventinganxiety in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing a pruritic condition in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing psychosis in an animal in need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glialcells of the central nervous system, particularly the brain, especiallyin the nucleus accumbens.

Methods for assaying cells that express mGluR5 are known in the art.

Applicants believe that the 3-substituted Pyridyl Compounds areantagonists for mGluR1.

The invention also relates to methods for inhibiting mGluR1 function ina cell, comprising contacting a cell capable of expressing mGluR1 withan amount of a 3-substituted Pyridyl Compound effective to inhibitmGluR1 function in the cell. This method can be used in vitro, forexample, as an assay to select cells that express mGluR1 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, UI, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression. Themethod is also useful for inhibiting mGluR1 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an amount of a 3-substituted Pyridyl Compound effective toinhibit mGluR1 function in the cell. In one embodiment, the method isuseful for treating or preventing pain in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing UIin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing an addictive disorder in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing Parkinson's disease in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingparkinsonism in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing anxiety in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing epilepsy in an animal in need thereof. In another embodiment,the method is useful for treating or preventing stroke in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a seizure in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a pruriticcondition in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing psychosis in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a cognitive disorder in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing amemory deficit in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing restricted brain function inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing Huntington's chorea in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing ALS in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing dementia in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing retinopathy in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a musclespasm in an animal in need thereof. In another embodiment, the method isuseful for treating or preventing a migraine in an animal in needthereof. In another embodiment, the method is useful for treating,preventing, or inhibiting vomiting in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingdyskinesia in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing depression in an animal inneed thereof.

Examples of cells capable of expressing mGluR1 include, but are notlimited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are known in the art.

4.6.1 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the 3-substituted Pyridyl Compounds areadvantageously useful in veterinary and human medicine. As describedabove, the 3-substituted Pyridyl Compounds are useful for treating orpreventing a Condition in an animal in need thereof.

When administered to an animal, the 3-substituted Pyridyl Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a 3-substituted Pyridyl Compound, can beadministered orally. The 3-substituted Pyridyl Compounds of theinvention can also be administered by any other convenient route, forexample, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral, rectal, and intestinalmucosa, etc.) and can be administered together with anothertherapeutically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, or capsules and can be used to administerthe 3-substituted Pyridyl Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of the 3-substituted Pyridyl Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer the3-substituted Pyridyl Compounds locally. This can be achieved, forexample, and not by way of limitation, by local infusion during surgery,topical application, e.g., in conjunction with a wound dressing aftersurgery, by injection, by means of a catheter, by means of a suppositoryor enema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the3-substituted Pyridyl Compounds into the central nervous system orgastrointestinal tract by any suitable route, includingintraventricular, intrathecal, and epidural injection, and enema.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the 3-substituted Pyridyl Compounds can beformulated as a suppository, with traditional binders and excipientssuch as triglycerides.

In another embodiment, the 3-substituted Pyridyl Compounds can bedelivered in a vesicle, in particular a liposome (see Langer, Science249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the 3-substituted Pyridyl Compounds can bedelivered in a controlled-release system or sustained-release system(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled- orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed.Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of the 3-substituted Pyridyl Compounds, e.g., thespinal column, brain, or gastrointestinal tract, thus requiring only afraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to an animal. Water is a particularlyuseful excipient when the 3-substituted Pyridyl Compound is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule (seee.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the 3-substituted Pyridyl Compounds are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

In another embodiment, the 3-substituted Pyridyl Compounds can beformulated for intravenous administration. Typically, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lidocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe 3-substituted Pyridyl Compounds are to be administered by infusion,they can be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where the 3-substitutedPyridyl Compounds are administered by injection, an ampule of sterilewater for injection or saline can be provided so that the ingredientscan be mixed prior to administration.

The 3-substituted Pyridyl Compounds can be administered bycontrolled-release or sustained-release means or by delivery devicesthat are known to those of ordinary skill in the art. Examples include,but are not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566,each of which is incorporated herein by reference. Such dosage forms canbe used to provide controlled- or sustained-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those of ordinary skill in the art, including those describedherein, can be readily selected for use with the active ingredients ofthe invention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled- orsustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained counterparts. In one embodiment, acontrolled- or sustained-release composition comprises a minimal amountof a 3-substituted Pyridyl Compound to cure or control the condition ina minimum amount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of the3-substituted Pyridyl Compound, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a 3-substituted Pyridyl Compound that promptly produces thedesired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the 3-substituted Pyridyl Compoundto maintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the3-substituted Pyridyl Compound in the body, the 3-substituted PyridylCompound can be released from the dosage form at a rate that willreplace the amount of 3-substituted Pyridyl Compound being metabolizedand excreted from the body. Controlled- or sustained-release of anactive ingredient can be stimulated by various conditions, including butnot limited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the 3-substituted Pyridyl Compound that is effective inthe treatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the Condition and can be decidedaccording to the judgment of a practitioner and/or each animal'scircumstances. Suitable effective dosage amounts, however, range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although they are typically about 100 mg/kg of body weight or less. Inone embodiment, the effective dosage amount ranges from about 0.01 mg/kgof body weight to about 100 mg/kg of body weight of a 3-substitutedPyridyl Compound, in another embodiment, about 0.02 mg/kg of body weightto about 50 mg/kg of body weight, and in another embodiment, about 0.025mg/kg of body weight to about 20 mg/kg of body weight. In oneembodiment, an effective dosage amount is administered about every 24 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 h until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 h until the Condition is abated. In anotherembodiment, an effective dosage amount is administered about every 6 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 4 h until the Condition isabated. The effective dosage amounts described herein refer to totalamounts administered; that is, if more than one 3-substituted PyridylCompound is administered, the effective dosage amounts correspond to thetotal amount administered.

Where a cell capable of expressing VR1, mGluR5 or mGluR1 is contactedwith a 3-substituted Pyridyl Compound in vitro, the amount effective forinhibiting the VR1, mGluR5 or mGluR1 receptor function in a cell willtypically range from about 0.01 μg/L to about 5 mg/L, in one embodiment,from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, fromabout 0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about0.01 μg/L to about 0.25 mg/L of a solution or suspension of apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the 3-substituted PyridylCompound is from about 0.01 μL to about 1 mL. In another embodiment, thevolume of solution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a 3-substituted Pyridyl Compound in vivo, the amount effective forinhibiting the receptor function in a cell will typically range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although it typically ranges from about 100 mg/kg of body weight orless. In one embodiment, the effective dosage amount ranges from about0.01 mg/kg of body weight to about 100 mg/kg of body weight of a3-substituted Pyridyl Compound, in another embodiment, about 0.020 mg/kgof body weight to about 50 mg/kg of body weight, and in anotherembodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of bodyweight. In one embodiment, an effective dosage amount is administeredabout every 24 h. In another embodiment, an effective dosage amount isadministered about every 12 h. In another embodiment, an effectivedosage amount is administered about every 8 h. In another embodiment, aneffective dosage amount is administered about every 6 h. In anotherembodiment, an effective dosage amount is administered about every 4 h.

The 3-substituted Pyridyl Compounds can be assayed in vitro or in vivofor the desired therapeutic or prophylactic activity prior to use inhumans. Animal model systems can be used to demonstrate safety andefficacy.

The present methods for treating or preventing a Condition in an animalin need thereof can further comprise administering to the animal beingadministered a 3-substituted Pyridyl Compound another therapeutic agent.In one embodiment, the other therapeutic agent is administered in aneffective amount.

The present methods for inhibiting VR1 function in a cell capable ofexpressing VR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR5 function in a cell capable ofexpressing mGluR5 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR1 function in a cell capable ofexpressing mGluR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is within the skilled artisan's purviewto determine the other therapeutic agent's optimal effective-amountrange. In one embodiment of the invention, where another therapeuticagent is administered to an animal, the effective amount of the3-substituted Pyridyl Compound is less than its effective amount wouldbe where the other therapeutic agent is not administered. In this case,without being bound by theory, it is believed that the 3-substitutedPyridyl Compound s and the other therapeutic agent act synergisticallyto treat or prevent a Condition.

The other therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, aβ-adrenergic blocker, an anticonvulsant, an antidepressant, aCa2+-channel blocker, an anticancer agent, an agent for treating orpreventing UI, an agent for treating or preventing an ulcer, an agentfor treating or preventing IBD, an agent for treating or preventing IBS,an agent for treating addictive disorder, an agent for treatingParkinson's disease and parkinsonism, an agent for treating anxiety, anagent for treating epilepsy, an agent for treating a stroke, an agentfor treating a seizure, an agent for treating a pruritic condition, anagent for treating psychosis, an agent for treating Huntington's chorea,an agent for treating ALS, an agent for treating a cognitive disorder,an agent for treating a migraine, an agent for treating vomiting, anagent for treating dyskinesia, or an agent for treating depression, andmixtures thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9 ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

The other therapeutic agent can also be an agent useful for reducing anypotential side effect of a 3-substituted Pyridyl Compounds. For example,the other therapeutic agent can be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine,acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide,bietanautine, bromopride, buclizine, clebopride, cyclizine,dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylatc, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasctron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycii; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazine;mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, andfelbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor,phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating, inhibiting, orpreventing vomiting include, but are not limited to, 5-HT₃ receptorantagonists such as odansteron, dolasetron, granisetron, andtropisetron; dopamine receptor antagonists such as prochlorperazine,thiethylperazine, chlorpromazin, metoclopramide, and domperidone;glucocorticoids such as dexamethasone; and benzodiazepines such aslorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A 3-substituted Pyridyl Compound and the other therapeutic agent can actadditively or, in one embodiment, synergistically. In one embodiment, a3-substituted Pyridyl Compound is administered concurrently with anothertherapeutic agent; for example, a composition comprising an effectiveamount of a 3-substituted Pyridyl Compound and an effective amount ofanother therapeutic agent can be administered. Alternatively, acomposition comprising an effective amount of a 3-substituted PyridylCompound and a different composition comprising an effective amount ofanother therapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a 3-substituted Pyridyl Compound isadministered prior or subsequent to administration of an effectiveamount of another therapeutic agent. In this embodiment, the3-substituted Pyridyl Compound is administered while the othertherapeutic agent exerts its therapeutic effect, or the othertherapeutic agent is administered while the 3-substituted PyridylCompound exerts its therapeutic effect for treating or preventing aCondition.

A composition of the invention is prepared by a method comprisingadmixing a 3-substituted Pyridyl Compound or a pharmaceuticallyacceptable salt and a pharmaceutically acceptable carrier or excipient.Admixing can be accomplished using methods known for admixing a compound(or salt) and a pharmaceutically acceptable carrier or excipient. In oneembodiment the 3-substituted Pyridyl Compound is present in thecomposition in an effective amount.

4.6.2 Kits

The invention encompasses kits that can simplify the administration of a3-substituted Pyridyl Compound to an animal.

A typical kit of the invention comprises a unit dosage form of a3-substituted Pyridyl Compound. In one embodiment, the unit dosage formis a container, which can be sterile, containing an effective amount ofa 3-substituted Pyridyl Compound and a pharmaceutically acceptablecarrier or excipient. The kit can further comprise a label or printedinstructions instructing the use of the 3-substituted Pyridyl Compoundto treat a Condition. The kit can also further comprise a unit dosageform of another therapeutic agent, for example, a second containercontaining an effective amount of the other therapeutic agent and apharmaceutically acceptable carrier or excipient. In another embodiment,the kit comprises a container containing an effective amount of a3-substituted Pyridyl Compound, an effective amount of anothertherapeutic agent and a pharmaceutically acceptable carrier orexcipient. Examples of other therapeutic agents include, but are notlimited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. Examples

Examples 1-5 relate to the synthesis of illustrative 3-substitutedPyridyl Compounds.

5.1 Example 1 Synthesis of Compound A19

To a solution of 0.1 g (0.43 mmol) of compound 1 (commercially availablefrom Maybridge Chemical Company Ltd., UK) in DCM (5 mL) was added 0.063g (0.43 mmol) of phenethylisocyanate 2 (commercially available fromSigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) and the resultingreaction mixture was stirred for about 4 h. at about 25° C. The solventwas removed under reduced pressure to provide a residue that waspurified using a silica gel column eluted with a gradient of 20:80 ethylacetate:hexane to 50:50 ethyl acetate:hexane to provide 3-substitutedPyridyl Compound A19 as a white solid (140 mg, 86% yield).

The identity of Compound A19 was confirmed using ¹H-NMR spectroscopy andmass spectrometry (MS).

Compound A19: ¹H-NMR (400 MHz, CD₃OD): δ 2.85 (t, 2H), 3.32 (bm, 4H),3.52-3.65 (m, 6H), 4.55 (bs, 1H), 7.05 (t, 1H), 7.21 (bm, 3H), 7.63 (t,2H), 7.93 (t, 1H), 8.49 (d, 1H).

MS (EI): m/z 378 (m+1).

5.2 Example 2 Synthesis of Compound A57

To a solution of 0.1 g (0.53 mmol) of compound 3 in DCM (5 mL) was added0.078 g (0.53 mmol) of phenethylisocyanate 2 (commercially availablefrom Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) and theresulting reaction mixture was stirred for about 4 h. at about 25° C.The solvent was removed under reduced pressure to provide a residue thatwas purified using a silica gel column eluted with a gradient of 20:80ethyl acetate:hexane to 50:50 ethyl acetate:hexane to provide3-substituted Pyridyl Compound A57 as a white solid (150 mg, 84% yield).

Compound 3 was obtained by dissolving 5 g of 2-chloro-3-cyano-pyridine(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)), 6.21 g of piperazine (72.16 mmol)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)), and 1.25 mL (72.16 mmol) of DIEA in DMF andallowing the resulting reaction mixture to stir for about 15 h. Waterand ethyl acetate were then added to the reaction mixture, the aqueousand organic phases separated, and the aqueous phase was extracted twicewith ethyl acetate. The combined ethyl acetate layers were then washedwith water, washed with brine, dried (Na₂ SO₄), and the solvent wasremoved under reduced pressure to provide a residue. The residue waspurified using a silica gel column to provide compound 3 (5.5 g, 81%).

The identity of Compound A57 was confirmed using ¹H-NMR spectroscopy andmass spectrometry.

Compound A57: ¹H-NMR (400 MHz, CD₃₀D): δ 2.85 (t, 2H), 3.52 (bm, 6H),3.75 (m, 4H), 4.55 (bs, 1H), 6.71 (t, 1H), 7.17-7.35 (bm, 5H), 7.70 (t,1H), 8.49 (d, 1H).

MS (EI): m/z 335 (m+1).

5.3 Example 3 Synthesis of Compound A38

To a solution of 0.1 g (0.48 mmol) of compound 4 in DCM (5 mL) was added0.071 g (0.48 mmol) of phenethylisocyanate 2 (commercially availablefrom Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) and theresulting reaction mixture was stirred for about 4 h. at about 25° C.The solvent was removed under reduced pressure to provide a residue thatwas purified using a silica gel column eluted with a gradient of 20:80ethyl acetate:hexane to 50:50 ethyl acetate:hexane to provide3-substituted Pyridyl Compound A38 as a white solid (145 mg, 85% yield).

Compound 4 was obtained by dissolving 5 g of 2-chloro-3-nitro-pyridine(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)), 8 g of piperazine (94.5 mmol) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)),and 12.21 mL (94.5 mmol) of DIEA in DMF and allowing the resultingreaction mixture to stir for about 15 h. Water and ethyl acetate werethen added to the reaction mixture, the aqueous and organic phasesseparated, and the aqueous phase was extracted twice with ethyl acetate.The combined ethyl acetate layers were then washed with water, washedwith brine, dried (Na₂ SO₄), and the solvent was removed under reducedpressure to provide a residue. The residue was purified using a silicagel column to provide compound 4 (5.2 g, 81%).

The identity of Compound A38 was confirmed using ¹H-NMR spectroscopy andmass spectrometry.

Compound A38: ¹H-NMR (400 MHz, CD₃₀D): δ 2.85 (t, 2H), 3.42-3.55 (bm,10H), 4.55 (bs, 1H), 6.75 (t, 1H), 7.15-7.25 (bm, 3H), 7.30-7.42 (bm,2H), 8.10 (t, 1H), 8.49 (d, 1H).

MS (EI): m/z 355 (m+1).

5.4 Example 4 Synthesis of Compound E19

Compound E19 was obtained by a method analogous to that described inExample 1.

The identity of Compound E19 was confirmed using ¹H-NMR spectroscopy andmass spectrometry.

Compound E19: ¹H-NMR (400 MHz, CD₃₀D): δ 8.48-8.43 (m, 1H), 7.92-7.87(m, 1H), 7.07-7.01 (m, 1H), 5.50 (bs, 1H), 4.50 (bs, 1H), 3.54-3.45 (m,4H), 3.37-3.25 (m, 6H), 2.21-2.13 (m, 2H), 2.06-1.91 (m, 4H), 1.70-1.52(m, 4H).

MS (EI): m/z=383.3.

5.5 Example 5 Synthesis of Compound I19

Compound I19 was obtained by a method analogous to that described inExample 1.

The identity of Compound I19 was confirmed using ¹H-NMR spectroscopy andmass spectrometry.

Compound 119: ¹H-NMR (400 MHz, CD₃₀D): δ 8.47-8.44 (m, 1H), 7.93-7.88(m, 1H), 7.02-7.01 (m, 1H), 4.43 (bs, 1H), 3.56-3.49 (m, 4H), 3.37-3.25(m, 6H), 1.78-1.62 (m, 6H), 1.47-1.40 (m, 2H), 1.38-1.10 (m, 4H),1.01-0.88 (m, 2H).

MS (EI): m/z=385.2.

5.6 Example 6 Binding of 3-Substituted Pyridyl Compounds to mGluR5

The following assay can be used to demonstrate that 3-substitutedPyridyl Compounds bind to mGluR5 and, accordingly, are useful fortreating or preventing, e.g., pain.

Cell cultures: Primary glial cultures are prepared from cortices ofSprague-Dawley 18 days old embryos. The cortices are dissected and thendissociated by trituration. The resulting cell homogenate is plated ontopoly-D-lysine precoated T175 flasks (BIOCOAT, commercially availablefrom Becton Dickinson and Company Inc. of Franklin Lakes, N.J.) inDulbecco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mMHEPES, and supplemented with 15% fetal calf serum (“FCS,” commerciallyavailable from Hyclone Laboratories Inc. of Omaha, Nebr.), and incubatedat 37° C. and 5% CO₂. After 24 hours, FCS supplementation is reduced to10%. On day six, oligodendrocytes and microglia are removed by stronglytapping the sides of the flasks. One day following this purificationstep, secondary astrocyte cultures are established by subplating onto 96poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes arewashed with serum free medium and then cultured in DMEM, withoutglutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermalgrowth factor (“EGF”), 1 mM sodium pyruvate, and 1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂.The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience 15(9):6103-6109 (1995).

Assay Protocol: After 3-5 days incubation with EGF, the astrocytes arewashed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂ PO₄, 2 mMCaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”)and loaded with the dye Fluo-4 (commercially available from MolecularProbes Inc. of Eugene, Oreg.) using 0.1 mL of Assay Buffer containingFluo-4 (3 mM final). After 90 minutes of dye loading, the cells are thenwashed twice with O₂ mL Assay Buffer and resuspended in 0.1 mL of AssayBuffer. The plates containing the astrocytes are then transferred to aFluorometric Imaging Plate reader (“FLIPR,” commercially available fromMolecular Devices Corporation of Sunnyvale, Calif.) for the assessmentof calcium mobilization flux in the presence of glutamate and in thepresence or absence of antagonist. After monitoring fluorescence for 15seconds to establish a baseline, DMSO solutions containing variousconcentrations of a 3-substituted Pyridyl Compound diluted in AssayBuffer (0.05 mL of 4× dilutions for competition curves) are added to thecell plate and fluorescence is monitored for 2 minutes. 0.05 mL of a 4×glutamate solution (agonist) is then added to each well to provide afinal glutamate concentration in each well of 10 mM. Plate fluorescenceis then monitored for an additional 60 seconds after agonist addition.The final DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine the IC₅₀ value. In eachexperiment, each data point is determined two times.

5.7 Example 7 In Vivo Assays for Prevention or Treatment of Pain

Test Animals Each experiment uses rats weighing between 200-260 g at thestart of the experiment. The rats are group-housed and have free accessto food and water at all times, except prior to oral administration of a3-substituted Pyridyl Compound when food is removed for 16 hours beforedosing. A control group acts as a comparison to rats treated with a3-substituted Pyridyl Compound. The control group is administered thecarrier for the 3-substituted Pyridyl Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand 3-substituted Pyridyl Compound administered to the test group.

Acute Pain: To assess the actions of the 3-substituted Pyridyl Compoundsfor the treatment or prevention of acute pain the rat tail flick testcan be used. Rats are gently restrained by hand and the tail exposed toa focused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a 3-substituted Pyridyl Compound. Data areexpressed as tail flick latency(s) and the percentage of the maximalpossible effect (% MPE), i.e., 20 seconds, is calculated as follows:

${\% \mspace{14mu} M\; P\; E} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {latency}} )} \rbrack}{( {20\mspace{14mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} )} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain: To assess the actions of the 3-substituted PyridylCompounds for the treatment or prevention of inflammatory pain theFreund's complete adjuvant (“FCA”) model of inflammatory pain is used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (L. Bartho et al., “Involvement ofCapsaicin-sensitive Neurones in Hyperalgesia and Enhanced OpioidAntinociception in Inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacol. 342:666-670 (1990)). The left hind paw of each animal isadministered a 50 μL intraplantar injection of 50% FCA. 24 hour postinjection, the animal is assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats are thenadministered a single injection of 1, 3, 10 or 30 mg/Kg of either a3-substituted Pyridyl Compound; 30 mg/Kg of a control selected fromCelebrex, indomethacin or naproxen; or carrier. Responses to noxiousmechanical stimuli are then determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack}{\lbrack {( {{baseline}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack} \times 100}$

Neuropathic Pain To assess the actions of the 3-substituted PyridylCompounds for the treatment or prevention of neuropathic pain either theSeltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.

Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack}{\lbrack {( {{baseline}\mspace{14mu} P\; W\; T} ) - ( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} )} \rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then be returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a 3-substitutedPyridyl Compound for the left rear paw of the animal. The animal canalso be assessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in S. H. Kim, “An Experimental Model for Peripheral NeuropathyProduced by Segmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32 (1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Only theaffected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

5.8 Example 8 In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be usedto assess the anxiolytic activity of 3-substituted Pyridyl Compounds inrats or mice.

The Elevated Plus Maze Test: The elevated plus maze consists of aplatform with 4 arms, two open and two closed (50×10×50 cm enclosed withan open roof). Rats (or mice) are placed in the center of the platform,at the crossroad of the 4 arms, facing one of the closed arms. Timespent in the open arms vs the closed arms and number of open arm entriesduring the testing period are recorded. This test is conducted prior todrug administration and again after drug administration. Test resultsare expressed as the mean time spent in open arms and the mean number ofentries into open arms. Known anxiolytic drugs increase both the timespent in open arms and number of open arm entries. The elevated plusmaze test is described in D. Treit, “Animal Models for the Study ofAnti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).

The Shock-Probe Burying Test: For the shock-probe burying test thetesting apparatus consists of a plexiglass box measuring 40×30×40 cm,evenly covered with approximately 5 cm of bedding material (odorabsorbent kitty litter) with a small hole in one end through which ashock probe (6.5 cm long and 0.5 cm in diameter) is inserted. Theplexiglass shock probe is helically wrapped with two copper wiresthrough which an electric current is administered. The current is set at2 mA. Rats are habituated to the testing apparatus for 30 min on 4consecutive days without the shock probe in the box. On test day, ratsare placed in one corner of the test chamber following drugadministration. The probe is not electrified until the rat touches itwith its snout or fore paws, at which point the rat receives a brief 2mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra.

5.9 Example 9 In Vivo Assays for Prevention or Treatment of an AddictiveDisorder

The conditioned place preference test or drug self-administration testcan be used to assess the ability of 3-substituted Pyridyl Compounds toattenuate the rewarding properties of known drugs of abuse.

The Conditioned Place Preference Test: The apparatus for the conditionedplace preference test consists of two large compartments (45×45×30 cm)made of wood with a plexiglass front wall. These two large compartmentsare distinctly different. Doors at the back of each large compartmentlead to a smaller box (36×18×20 cm) box made of wood, painted grey, witha ceiling of wire mesh. The two large compartments differ in terms ofshading (white vs black), level of illumination (the plexiglass door ofthe white compartment is covered with aluminum foil except for a windowof 7×7 cm), texture (the white compartment has a 3 cm thick floor board(40×40 cm) with nine equally spaced 5 cm diameter holes and the blackhas a wire mesh floor), and olfactory cues (saline in the whitecompartment and 1 mL of 10% acetic acid in the black compartment). Onhabituation and testing days, the doors to the small box remain open,giving the rat free access to both large compartments.

The first session that a rat is placed in the apparatus is a habituationsession and entrances to the smaller grey compartment remain open givingthe rat free access to both large compartments. During habituation, ratsgenerally show no preference for either compartment. Followinghabituation, rats are given 6 conditioning sessions. Rats are dividedinto 4 groups: carrier pre-treatment+carrier (control group),3-substituted Pyridyl Compound pre-treatment+carrier, carrierpre-treatment+morphine, 3-substituted Pyridyl Compoundpre-treatment+morphine. During each conditioning session the rat isinjected with one of the drug combinations and confined to onecompartment for 30 min. On the following day, the rat receives acarrier+carrier treatment and is confined to the other largecompartment. Each rat receives three conditioning sessions consisting of3 drug combination-compartment and 3 carrier-compartment pairings. Theorder of injections and the drug/compartment pairings arecounterbalanced within groups. On the test day, rats are injected priorto testing (30 min to 1 hour) with either morphine or carrier and therat is placed in the apparatus, the doors to the grey compartment remainopen and the rat is allowed to explore the entire apparatus for 20 min.The time spent in each compartment is recorded. Known drugs of abuseincrease the time spent in the drug-paired compartment during thetesting session. If the 3-substituted Pyridyl Compound blocks theacquisition of morphine conditioned place preference (reward), therewill be no difference in time spent in each side in rats pre-treatedwith a 3-substituted Pyridyl Compound and the group will not bedifferent from the group of rats that was given carrier+carrier in bothcompartments. Data will be analyzed as time spent in each compartment(drug combination-paired vs carrier-paired). Generally, the experimentis repeated with a minimum of 3 doses of a 3-substituted PyridylCompound.

The Drug Self-Administration Test: The apparatus for the drugself-administration test is a standard commercially available operantconditioning chamber. Before drug trials begin rats are trained to pressa lever for a food reward. After stable lever pressing behavior isacquired, rats are tested for acquisition of lever pressing for drugreward. Rats are implanted with chronically indwelling jugular cathetersfor i.v. administration of compounds and are allowed to recover for 7days before training begins. Experimental sessions are conducted dailyfor 5 days in 3 hour sessions. Rats are trained to self-administer aknown drug of abuse, such as morphine. Rats are then presented with twolevers, an “active” lever and an “inactive” lever. Pressing of theactive lever results in drug infusion on a fixed ratio 1 (FR1) schedule(i.e., one lever press gives an infusion) followed by a 20 second timeout period (signaled by illumination of a light above the levers).Pressing of the inactive lever results in infusion of excipient.Training continues until the total number of morphine infusionsstabilizes to within ±10% per session. Trained rats are then used toevaluate the effect of 3-substituted Pyridyl Compounds pre-treatment ondrug self-administration. On test day, rats are pre-treated with a3-substituted Pyridyl Compound or excipient and then are allowed toself-administer drug as usual. If the 3-substituted Pyridyl Compoundblocks the rewarding effects of morphine, rats pre-treated with the3-substituted Pyridyl Compound will show a lower rate of respondingcompared to their previous rate of responding and compared to excipientpre-treated rats. Data is analyzed as the change in number of druginfusions per testing session (number of infusions during test session-number of infusions during training session).

5.10 Example 10 Functional Assay for Characterizing mGluR1AntagonisticProperties

Functional assays for the characterization of mGluR 1 antagonisticproperties are known in the art. For example, the following procedurecan be used.

A CHO-rat mGluR1 cell line is generated using cDNA encoding rat mGluR1receptor (M. Masu and S. Nakanishi, Nature 349:760-765 (1991)). The cDNAencoding rat mGluR1 receptor can be obtained from, e.g., Prof. S.Nakanishi (Kyoto, Japan).

40,000 CHO-rat mGluR1 cells/well are plated into a COSTAR 3409, black,clear bottom, 96 well, tissue culture treated plate (commerciallyavailable from Fisher Scientific of Chicago, Ill.) and are incubated inDulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented withglutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12h. The CHO-rat mGluR1 cells are then washed and treated with OPTIMEMmedium (commercially available from Invitrogen, Carlsbad, Calif.) andincubated for a time period ranging from 1 to 4 hours prior to loadingthe cells with the dye FLUO-4 (commercially available from MolecularProbes Inc., Eugene, Oreg.). After incubation, the cell plates arewashed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 μM,NaH₂ PO₄, 2 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, and 10 mM glucose, pH7.4) and incubated with 3 M FLUO-4 in 0.1 mL loading buffer for 90 min.The cells are then washed twice with 0.2 mL loading buffer, resuspendedin 0.1 mL of loading buffer, and transferred to a FLIPR for measurementof calcium mobilization flux in the presence of glutamate and in thepresence or absence of a 3-substituted Pyridyl Compound.

To measure calcium mobilization flux, fluoresence is monitored for about15 s to establish a baseline and DMSO solutions containing variousconcentrations of a 3-substituted Pyridyl Compound ranging from about 50μM to about 0.8 nM diluted in loading buffer (0.05 mL of a 4× dilution)are added to the cell plate and fluorescence is monitored for about 2min. 0.05 mL of a 4× glutamate solution (agonist) is then added to eachwell to provide a final glutamate concentration in each well of 10 μMand fluorescence is monitored for about 1 additional min. The final DMSOconcentration in the assay is 1%. In each experiment fluorescence ismonitored as a function of time and the data is analyzed using anon-linear regression to determine the IC₅₀ value. In each experimenteach data point is determined twice.

5.11 Example 11 Binding of 3-Substituted Pyridyl Compounds to VR1

Methods for assaying compounds capable of inhibiting VR1 are known tothose skilled in the art, for example, those methods disclosed in U.S.Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 toMcIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al. The resultsof these assays will demonstrate that 3-substituted Pyridyl Compoundsbind to and modulate the activity of VR1.

Binding of Compound A19 to VR1 Assay Protocol

Human VR1Cloning: Human spinal cord RNA (commercially available fromClontech, Palo Alto, Calif.) was used. Reverse transcription wasconducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase(commercially available from Invitrogen, Carlsbad, Calif.) and oligo dTprimers as detailed in its product description. Reverse transcriptionreactions were incubated at 55° C. for 1 h, heat-inactivated at 85° C.for 5 min, and RNase H-treated at 37° C. for 20 min.

Human VR1 cDNA sequence was obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences were removed and flanking exonic sequences were joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human VR1 were designed as follows: forward primer,GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer,GAAGATCTTCGGGGACAGTGACGGTTGGATGT.

PCR of VR1 was performed on one tenth of the Reverse transcriptionreaction mixture using Expand Long Template Polymerase and Expand Buffer2 in a final volume of 50 μL according to the manufacturer'sinstructions (Roche Applied Sciences, Indianapolis, Ind.). Afterdenaturation at 94° C. for 2 min PCR amplification was performed for 25cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68° C. for 3 minfollowed by a final incubation at 72° C. for 7 min to complete theamplification. A PCR product of ˜2.8 kb was gel-isolated using a 1.0%agarose, Tris-Acetate gel containing 1.6 g/mL of crystal violet andpurified with a S.N.A.P. UV-Free Gel Purification Kit (commerciallyavailable from Invitrogen). The VR1 PCR product was cloned into thepIND/V5-His-TOPO vector (commercially available from Invitrogen)according to the manufacturer's instructions. DNA preparations,restriction enzyme digestions, and preliminary DNA sequencing wereperformed according to standard protocols. Full-length sequencingconfirmed the identity of the human VR1.

Generation of Inducible Cell Lines: Unless noted otherwise, cell culturereagents were purchased from Life Technologies of Rockville, Md.HEK293-EcR cells expressing the ecdysone receptor (commerciallyavailable from Invitrogen) were cultured in Growth Medium (Dulbecco'sModified Eagles Medium containing 10% fetal bovine serum (commerciallyavailable from HYCLONE, Logan, Utah), 1× penicillin/streptomycin, 1×glutamine, 1 mM sodium pyruvate and 400 g/mL Zeocin (commerciallyavailable from Invitrogen)). The VR1-pIND constructs were transfectedinto the HEK293-EcR cell line using Fugene transfection reagent(commercially available from Roche Applied Sciences, Basel,Switzerland). After 48 h, cells were transferred to Selection Medium(Growth Medium containing 300 μg/mL G418 (commercially available fromInvitrogen)). Approximately 3 weeks later individual Zeocin/G418resistant colonies were isolated and expanded. To identify functionalclones, multiple colonies were plated into 96-well plates and expressionwas induced for 48 h using Selection Medium supplemented with 5 μMponasterone A (“PonA”) (commercially available from Invitrogen). On theday of assay, cells were loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx was measured using a FLIPR as describedbelow. Functional clones were re-assayed, expanded, and cryopreserved.

pH-Based Assay: Two days prior to performing this assay, cells wereseeded on poly-D-lysine-coated 96-well clear-bottom black plates(commercially available from Becton-Dickinson) at 75,000 cells/well ingrowth media containing 5 μM PonA (commercially available fromInvitrogen) to induce expression. On the day of the assay, the plateswere washed with 0.2 mL 1× Hank's Balanced Salt Solution (commerciallyavailable from Life Technologies) containing 1.6 mM CaCl₂ and 20 mMHEPES, pH 7.4 (“wash buffer”), and loaded using 0.1 mL of wash buffercontaining Fluo-4 (3 μM final concentration, commercially available fromMolecular Probes). After 1 h, the cells were washed twice with 0.2 mLwash buffer and resuspended in 0.05 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 3.5 mM CaCl₂and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates were then transferredto a FLIPR (commercially available from Molecular Devices) for assay.Compound A19 was diluted in assay buffer, and 50 mL of the resultantsolution were added to the cell plates and the solution monitored fortwo minutes. The final concentration of Compound A19 ranged from about50 pM to about 3 μM. Agonist buffer (wash buffer titrated with 1N HCl toprovide a solution having a pH of 5.5 when mixed 1:1 with assay buffer)(0.1 mL) was then added to each well, and the plates were incubated for1 additional minute. Data were collected over the entire time course andanalyzed using Excel and Graph Pad Prism. Compound A19 when assayedaccording to this protocol had an IC₅₀ of 808.2±253.7 nM (n=5).

Capsaicin-based Assay: Two days prior to performing this assay, cellswere seeded in poly-D-lysine-coated 96-well clear-bottom black plates(50,000 cells/well) in growth media containing 5 μM PonA (commerciallyavailable from Invitrogen) to induce expression. On the day of theassay, the plates were washed with 0.2 mL 1× Hank's Balanced SaltSolution (commercially available from Life Technologies) containing 1 mMCaCl₂ and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL ofwash buffer containing Fluo-4 (3 μM final). After one hour, the cellswere washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mLof wash buffer. The plates were transferred to a FLIPR (commerciallyavailable from Molecular Devices) for assay. 50 μL of Compound A19diluted with assay buffer were added to the cell plates and incubatedfor 2 min. The final concentration of Compound A19 ranged from about 50μM to about 3 μM. Human VR1 was activated by the addition of 50 μL ofcapsaicin (400 nM), and the plates were incubated for an additional 3min. Data were collected over the entire time course and analyzed usingExcel and GraphPad Prism. Compound A19 when assayed according to thisprotocol had an IC₅₀ of 382±64.2 nM (n=3).

The results of the pH-based assay and the capsaicin-based assaydemonstrate that Compound A19, an illustrative 3-substituted PyridylCompound, binds to and modulates the activity of human VR1 andaccordingly is useful for treating or preventing pain, UI, an ulcer,IBD, or IBS in an animal.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; Ar₂is

R₁ is —CF₃, —NO₂, or —CN; each R₂ is independently —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups;each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂; (b)—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups; or(c)-phenyl, -naphthyl, —(C₁₄)aryl, or -(5- to 10-membered)heteroaryl,each of which is unsubstituted or substituted with one or more R₆groups; each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇ OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇; each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂ (halo), —CN, —OH,-halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₇ is independently —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂ (halo); each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂ (halo); each R₉ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂ (halo), —CN,—OH, -halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₁₁ is independently —CN,—OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -halo, —N₃, —NO₂,—N(R)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇,—SR₇, —S(O)R₇, or —S(O)₂R₇; each halo is independently —F, —Cl, —Br, or—I; n is 1 or 2; m is 0 or 1; q is an integer ranging from 0 to 6; r isan integer ranging from 0 to 5; t is an integer ranging from 0 to 2; andv is 0 or
 1. 2. The compound of claim 1, wherein R₁ is —CF₃.
 3. Thecompound of claim 2, wherein n is
 1. 4. The compound of claim 3, whereinR₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.
 5. Thecompound of claim 4, wherein: X is O; m is 0; and t is
 0. 6. Thecompound of claim 5, wherein Ar₂ is phenyl and r is
 0. 7. The compoundof claim 5, wherein Ar₂ is phenyl, r is 1, 2, 3, 4, or 5, and the Ar₂phenyl is substituted at its 4-position with an R₉ group.
 8. Thecompound of claim 7, wherein each R₉ group is independently selectedfrom —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃, -iso-propoxy, -tert-butoxy, —OCF₃,and —(C₁-C₆)alkyl.
 9. The compound of claim 8, wherein eachR₉—(C₁-C₆)alkyl group is independently selected from —CH₃, -n-propyl,-iso-propyl, -n-butyl, -iso-butyl, -sec-butyl, and -tert-butyl.
 10. Thecompound of claim 4, wherein: X is O; m is 1; R₃ is —CH₃; and t is 0.11. The compound of claim 10, wherein Ar₂ is phenyl and r is
 0. 12. Thecompound of claim 10, wherein Ar₂ is phenyl, r is 1, 2, 3, 4, or 5, andthe Ar₂ phenyl is substituted at its 4-position with an R₉ group. 13.The compound of claim 12, wherein each R₉ group is independentlyselected from —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃, -iso-propoxy,-tert-butoxy, —OCF₃, and —(C₁-C₆)alkyl.
 14. The compound of claim 13,wherein each R₉ —(C₁-C₆)alkyl group is independently selected from —CH₃,-n-propyl, -iso-propyl, -n-butyl, -iso-butyl, -sec-butyl, and-tert-butyl.
 15. The compound of claim 1, wherein R₁ is —NO₂.
 16. Thecompound of claim 15, wherein n is
 1. 17. The compound of claim 16,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.18. The compound of claim 17, wherein: X is O; m is 0; and t is
 0. 19.The compound of claim 18, wherein Ar₂ is phenyl and r is
 0. 20. Thecompound of claim 18, wherein Ar₂ is phenyl, r is 1, 2, 3, 4, or 5, andthe Ar₂ phenyl is substituted at its 4-position with an R₉ group. 21.The compound of claim 20, wherein each R₉ group is independentlyselected from —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃, -iso-propoxy,-tert-butoxy, —OCF₃, and —(C₁-C₆)alkyl.
 22. The compound of claim 21,wherein each R₉ —(C₁-C₆)alkyl group is independently selected from —CH₃,-n-propyl, -iso-propyl, -n-butyl, -iso-butyl, -sec-butyl, and-tert-butyl.
 23. The compound of claim 17, wherein: X is O; m is 1; R₃is —CH₃; and t is
 0. 24. The compound of claim 23, wherein Ar₂ is phenyland r is
 0. 25. The compound of claim 23, wherein Ar₂ is phenyl, r is 1,2, 3, 4, or 5, and the Ar₂ phenyl is substituted at its 4-position withan R₁ group.
 26. The compound of claim 25, wherein each R₉ group isindependently selected from —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃,-iso-propoxy, -tert-butoxy, —OCF₃, and —(C₁-C₆)alkyl.
 27. The compoundof claim 26, wherein each R₉ —(C₁-C₆)alkyl group is independentlyselected from —CH₃, -n-propyl, -iso-propyl, -n-butyl, -iso-butyl,-sec-butyl, and -tert-butyl.
 28. The compound of claim 1, wherein R₁ is—CN.
 29. The compound of claim 28, wherein n is
 1. 30. The compound ofclaim 29, wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅groups.
 31. The compound of claim 30, wherein: X is O; m is 0; and t is0.
 32. The compound of claim 31, wherein Ar₂ is phenyl and r is
 0. 33.The compound of claim 31, wherein Ar₂ is phenyl, r is 1, 2, 3, 4, or 5,and the Ar₂ phenyl is substituted at its 4-position with an R₉ group.34. The compound of claim 33, wherein each R₉ group is independentlyselected from —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃, -iso-propoxy,-tert-butoxy, —OCF₃, and —(C₁-C₆)alkyl.
 35. The compound of claim 34,wherein each R₉ —(C₁-C₆)alkyl group is independently selected from —CH₃,-n-propyl, -iso-propyl, -n-butyl, -iso-butyl, -sec-butyl, and-tert-butyl.
 36. The compound of claim 30, wherein: X is O; m is 1; R₃is —CH₃; and t is
 0. 37. The compound of claim 36, wherein Ar₂ is phenyland r is
 0. 38. The compound of claim 36, wherein Ar₂ is phenyl, r is 1,2, 3, 4, or 5, and the Ar₂ phenyl is substituted at its 4-position withan R₉ group.
 39. The compound of claim 38, wherein each R₉ group isindependently selected from —CF₃, —CH₂CF₃, —Cl, —Br, —OCH₃,-iso-propoxy, -tert-butoxy, —OCF₃, and —(C₁-C₆)alkyl.
 40. The compoundof claim 39, wherein each R₉—(C₁-C₆)alkyl group is independentlyselected from —CH₃, -n-propyl, -iso-propyl, -n-butyl, -iso-butyl,-sec-butyl, and -tert-butyl.
 41. The compound of claim 1, wherein Ar₂is:


42. A composition comprising an effective amount of the compound or apharmaceutically acceptable salt of the compound of claim 1 and apharmaceutically acceptable carrier or excipient.
 43. A method forinhibiting VR1 function in a cell comprising contacting a cell, capableof expressing VR1 with an effective amount of the compound or apharmaceutically acceptable salt of the compound of claim
 1. 44. Amethod for treating pain in an animal, comprising administering to ananimal in need thereof an effective amount of the compound or apharmaceutically acceptable salt of the compound of claim 1 and,optionally, an effective amount of another therapeutic agent.